CHAPTER 3: TRANSLATING HUMAN GENOMIC
RESEARCH INTO CLINICAL PRACTICE
The framework for translational
research in the UK
3.1. "Translational research" is the
research which bridges the gap between basic or clinical research
and the application of innovations in a healthcare setting. It
is vital to realising the potential of genomic medicine. Examples
include developing diagnostic tests to a marketable product and
research to assess their clinical utility (that is, their benefit
to patients).
THE COOKSEY REVIEW
3.2. In a White Paper published in 2003, Our
inheritance, our future: realising the potential of genetics in
the NHS (Cm 5791) ("the 2003 Genetics White Paper"),
the Government outlined their vision for the NHS in the context
of genetic science. It was:
"… to lead the world in taking maximum
advantage of the safe, effective and ethical application of the
new genetic knowledge and technologies as soon as they become
available".
3.3. But Sir David Cooksey, in his 2006
Review of UK Health Research Funding ("the Cooksey
Review"), identified translational research as an
area of weakness and warned that the UK was at risk of failing
to reap the full economic, health and social benefits that public
investment in health research should generate. Two key gaps were
identified: first, the translation of ideas from basic or clinical
research into development of new products and new approaches to
treatment of disease and illness; and, second, the use of those
new products and approaches in clinical practice. In this chapter
we focus on the first of these gaps.
3.4. The Cooksey Review identified a range of
cultural, institutional and financial barriers to the translation
of publicly-funded research into clinical practice and made a
number of recommendations to overcome them. They included:
- better co-ordination of health research and coherent
funding arrangements to support translation through the establishment
of an Office for the Strategic Co-ordination of Health Research
(OSCHR) to co-ordinate research between the National Institute
for Health Research (NIHR) and the Medical Research Council (MRC)
and to monitor progress; and
- the inclusion of additional funding streams in
ring-fenced funding for Department of Health (DoH) research, and
additional funding in key areas including Health Technology Assessments
(HTAs) to support the uptake of new ideas and technologies.
In 2007, the Government set up OSCHR in accordance
with the review recommendation.
3.5. Since its creation, OSCHR has been responsible
for the co-ordination of public sector health research in the
UK, estimated to be worth £1.7 billion a year by 2010-11.
Its partners, the NIHR and MRC, have jointly developed a new approach
to translational research, including a more coherent funding arrangement
which involves each organisation taking the lead on funding for
core activities (the MRC for early development of new opportunities
from discovery research and development to early-stage clinical
trials and the NIHR for large-scale clinical trials). The recent
injection of funding through OSCHR for translational research
has, according to Professor Peter Donnelly, Director of the
Wellcome Trust Centre for Human Genetics at the University of
Oxford, "had an extremely positive impact" on translational
research (p 79). We commend this strategic and co-ordinated
approach to translational research and the work of OSCHR in achieving
this co-ordination.
3.6. None the less, OSCHR's first progress report,
published in November 2008, indicated that significant challenges
remain; and the recent report by the Bioscience Innovation and
Growth Team, The Review and Refresh of Bioscience 2015,
published in January 2009, confirmed this: "despite all of
the activity [to improve the translation of health research into
clinical applications] …, the adoption of new therapies,
drugs and procedures in the NHS remains painfully slow …
and the translation of these improvements into patient benefit
has not yet materialised".[8]
As for genomic medicine in particular, the Foundation for Genomics
and Population Health ("the PHG Foundation") told us
that although genomic science was in a "robust state",
"progress is dramatically slower in evaluating the clinical
and public health relevance of these scientific advances and in
developing systems for effective translation of validated tests
and interventions into clinical practice" (p 134). Oxford
Nanopore expressed a similar view (p 325).
Funding and translational research
in genomic medicine
3.7. In the 2003 Genetics White Paper, the Government
made a commitment to provide £50 million to help the NHS
make better use of advances in genetic science. This included
investing £18 million capital on upgrading NHS genetics laboratory
facilities, £2 million "start-up" funding over
three years for initiatives to bring the benefits of genetics
into mainstream practice, £15 million to support the development
of five genetics knowledge parks over five years, and £2.5
million for pharmacogenetic research into existing medicines.
The Government also made a commitment to ensure that the necessary
infrastructure (such as informatics and laboratory services) was
in place and that training was available to support translational
research. In April 2008, the Government published a review of
the 2003 White Paper—Genetics White Paper Review 2008
("the 2008 Review"). (The White Paper and Review
are considered further in Chapter 4.)
3.8. Although the Government has now fulfilled
many of the objectives set out in the 2003 White Paper, a number
of witnesses expressed concern about whether the funding commitments
were sufficiently long-term. The Research Councils UK (RCUK),
for example, warned that the "high level of investment [set
out in the White Paper] … will need to be maintained to ensure
that the developing understanding feeds through into benefits
for clinical care and public health" (p 1). According
to Oxford Nanopore: "It is essential that the investment
in genetics is part of a long-term strategy to support innovation
in the field and not a one-off event" (p 325); and the
Wellcome Trust Sanger Institute referred to the importance of
having a "strategic vision and sustained investment"
(p 328). It is perhaps reassuring therefore that the need
for sustained funding was acknowledged in the 2008 Review that
genetics is still a relatively new area of work, and the review
recognises that developments need to be considered over a longer
timeframe, and will require sustained support.[9]
3.9. When asked about the Government's plans
to extend the programmes set out in the 2003 Genetics White Paper,
the Minister of State for Public Health, Dawn Primarolo MP,
said:
"Both the MRC and NIHR have new funding
streams supporting … translational research … We have
also invested more money in the NIHR's health technology investment
programme, and that programme has recently put out a themed call
for the evaluation of diagnostic tests, and on top of that the
Department of Health, with the Wellcome Trust, has the Health
Innovation Challenge Fund, which will have a big part to play
… [we have] recently appointed Professor John Burn from
the Newcastle Centre for Life as Chair of the National Clinical
Genetics Specialty Group … responsible for facilitating and
encouraging timely development and, building on this, we plan
to award £100,000 a year to the University of Newcastle under
the direction of Professor Burn to enable clinical geneticists
to come together and to identify current research activity and
new funding opportunities" (Q 857).
3.10. Although we welcome these initiatives,
we question whether they amount to a sufficiently strategic, long-term
approach to funding translational research into genomic science.
Recognising this deficiency, Professor Sir Alex Markham,
Chair of OSCHR Translation Medicine Board, suggested that OSCHR
had a role to play in remedying it:
"OSCHR should be charged to make sure that
there is some strategic thinking going on constantly about genetics
and its place in the health system. The structures that have been
built over the last 12-18 months in and around OSCHR are well
designed to do that … I think we have an oversight capacity
now that we have never had in this country before to take the
hot science into the clinic when appropriate" (Q 474).
3.11. On 4 November 2008, the Prime Minister,
Gordon Brown MP, asked OSCHR to work with the Department
of Health (DoH) and the Department for Innovation, Universities
and Skills (DIUS), through the MRC, NIHR and the research community,
to identify a set of National Ambitions for Translational Health
Research, with a view to developing an overarching set of national
objectives to encourage the translation of major research breakthroughs
into new NHS treatments and services within a decade. As part
of this initiative, we recommend that OSCHR should take the
lead in developing a strategic vision for genomic medicine in
the UK with a view to ensuring the effective translation of basic
and clinical genomic research into clinical practice.
3.12. This strategic vision should form the
basis of a new Government White Paper on genomic medicine which
should outline:
- the measures the Department of Health will
take in order to facilitate the translation of advances in genomic
science into clinical practice;
- a roadmap for how such developments will be
incorporated into the NHS; and
- proposals for a programme of sustained long-term
funding to support such measures.
Strategies to facilitate translational
research in the NHS
CULTURE CHANGE WITHIN THE NHS
3.13. In his Foreword to OSCHR's first progress
report, Professor Sir John Bell suggested that real
commitment to research was still lacking in most NHS trusts, something
that had to change if a culture of innovation in the NHS were
to develop. The final report of Lord Darzi of Denham's NHS Next
Stage Review, High Quality Care for All ("the final
report"), published in June 2008, proposed placing
a legal duty on Strategic Health Authorities (SHAs) to foster
and promote innovation which, in addition to other initiatives
to encourage translation in the NHS, was intended to encourage
cultural change. Commenting on that report, Professor Sir John
Bell told us that although it was helpful that the NHS constitution
was going to have within it a commitment with regard to research,
"there needs to be central management to make sure that it
is a main pillar of the whole organisation" (Q 453).
Whilst acknowledging this caution, we are encouraged by recent
developments with regard to cultural change within the NHS.
MAKING THE CONDUCT OF CLINICAL TRIALS LESS BURDENSOME
3.14. The UK Clinical Research Collaboration
was established in 2004 to streamline applications for clinical
trials. It has led to significant improvements in the applications
process. These include setting up an infrastructure to conduct
clinical research in the NHS through the national clinical research
networks and the provision of an advisory service and model agreements
for clinical trials. The establishment of the Integrated Research
Application System in 2008, in conjunction with the National Research
Ethics Service, which provides for one data entry point for applications,
has also received positive feedback from the research community.
3.15. However, it appears that the process for
the establishment of clinical trials in the NHS remains burdensome,
in particular because of the way in which the EU Clinical Trials
Directive has been applied in the UK, and also because of the
complexities surrounding confidentiality and consent in the sharing
of medical data for research purposes (see Chapter 6). The
Review and Refresh of Bioscience 2015 report noted that the
proportion of UK patients in global trials fell from six per cent
in 2002 to two per cent in 2006, and suggested that, although
the EU Clinical Trials Directive aimed to simplify and harmonise
the rules governing clinical trials in the EU, the opposite had
in fact been achieved; and, it was further suggested, differences
amongst member states in applying the Directive had made the UK
an increasingly unattractive location for biotechnology businesses
to conduct research.[10]
3.16. The Association of the British Pharmaceutical
Industry (ABPI) also referred to difficulties with the clinical
trials process, including the "slow start-up of trials and
recruitment of patients." (p 369); and Professor Collins
told us:
"The regulatory obstacles to the use of
medical records, and the regulatory burden for clinical trials
as a consequence of the EU Directive on clinical trials and its
implementation into UK law, have pushed research and research
funding out of the UK … The consequence of these, and also
of NHS research governance, is that our ability to do this kind
of research has been made increasingly difficult and costly, and
research is being slowed substantially" (Q 527).
3.17. We recommend that the Government revises
the UK implementation of the EU Clinical Trials Directive, in
consultation with the research community, to make it less burdensome
for researchers.
3.18. The European Commission is currently considering
whether the EU Clinical Trials Directive should be reviewed in
2010. The Review and Refresh of Bioscience 2015 report
urges the UK to take a leadership role in any revision of the
Directive to ensure consistency and to prevent the UK continuing
to be an unattractive place, for both regulatory and financial
reasons, to conduct research.[11]
If the European Commission decides in favour of a review of
the EU Clinical Trials Directive in 2010, we urge the Government
to participate fully in discussions in order to ensure that the
revised Directive is less burdensome for researchers.
PROMOTING COLLABORATIVE TRANSLATIONAL RESEARCH BETWEEN
INDUSTRY, ACADEMIA, THE CHARITABLE SECTOR AND THE NHS
3.19. According to a recent ABPI survey, "the
volume of collaborations declined between 2003 and 2007".
From the industry's perspective, the ABPI cited "escalating
cost, increasing international competition for research funds,
difficulty in contract negotiation and lack of incentives available
for academics to collaborate more closely with industry"
as barriers to collaborative research and noted that "if
the UK is to have the best chance to lead in genomic medicine,
these issues should be addressed" (p 367).
3.20. With regard to the involvement of academia,
the Human Genetics Commission (HGC) noted that "certain conditions—such
as the cost of postdoctoral funding in the UK and level of incentive
for academics to collaborate with industry on research projects
under the proposed Research Excellence Framework—are not
currently optimised for collaboration between the pharmaceutical
industry and academia" (p 161). This view was echoed
in a recent Nature article in which the University of Oxford
stated that "it is not financially viable" to participate
in the Innovative Medicines Initiative, a major new initiative
to fund European public-private partnerships, due to the funding
terms of the initiative.[12]
3.21. Professor Pirmohamed agreed that escalating
costs inhibited collaboration with industry. He suggested that
recent changes in funding mechanisms were part of the problem.
The move to Full Economic Costing in April 2006 has meant that
industry has had to pay for 100 per cent of the direct costs (for
example, laboratory supplies for a project or the salary of a
scientist to run it) and the indirect costs (for example, a proportion
of the maintenance cost for university facilities) for each individual
project, or their proportionate share of the direct and indirect
costs of a collaborative project. According to Professor Pirmohamed,
"it has made a difference to us in terms of full economic
costing in that certain companies have walked away because of
the additional costs" (Q 746).
3.22. There is also a lack of incentive for the
NHS to take part in research collaboration. The Institute of Medical
Genetics (IMG) told us:
"Co-operation between industry and the NHS
is essential, but NHS resources to collaborate with industry are
at best miniscule, if only because actual and perceived rules,
such as commissioners not being allowed to fund 'R&D', create
huge barriers to progress. If R&D were regarded more as R, D & S,
indicating 'Research, Development and Service', that might help
break down this barrier. Research then would be thought more of
the remit of research funding bodies, and D&S rightly the
remit of the NHS" (p 247).
3.23. The charitable sector is also discouraged
from collaborating. We were told by the Breast Cancer Campaign
that "there is presently no initiative to involve all funders
of research in collaboration, and we believe that this will continue
to slow down advancement across all areas of research" (p 500).
3.24. Although there seem to be so many practical
disincentives to collaboration, the industry and others acknowledge
its significance in principle. For example, the pharmaceutical
company, Astrazeneca, said:
"Progress in genomic medicine and translation
to clinical practice will require an integrated approach between
stakeholders; including scientists to discover and develop biomarkers,
diagnostic companies to develop enabling technology to test the
biomarkers, pharmaceutical companies to conduct clinical trials
demonstrating the clinical utility of the diagnostics and the
healthcare system to translate the linked drugs and diagnostics
to clinical practice" (p 477).
The Academy of Medical Sciences (AMS) endorsed this
view:
"Extensive collaboration is required between
pharmaceutical companies, academia and the regulatory authorities
to validate new technologies [for genomic medicine]. This will
require companies to share safety data and to engage in new pre-competitive
joint research in the UK and internationally" (p 467).
3.25. The DoH and the ABPI have worked closely
to develop the concept of "joint working" between the
NHS and the pharmaceutical industry, and have issued best practice
guidelines for NHS staff and a supporting best practice "toolkit".
The Royal College of Physicians is also preparing a report on
promoting collaborative working; and the Minister for Science
and Innovation, Lord Drayson, told us:
"[It is] central to the effect and development
of innovative medicines and … in particular in the case of
developments from the field of genomics is the vital importance
of this public/private partnership and the relationship between
the academic research base, the NHS and the early stage development
into the large pharmaceutical industry … The MRC … just
this week … is launching a new collaborative scheme".
But, he concluded, "we need to do more'"
(Q 903).
3.26. Whilst we welcome the new MRC collaborative
scheme, we are aware that the 2006 Cooksey Review recommended
that OSCHR should also encourage greater collaboration to facilitate
the translation of scientific advances into clinical applications.
We recommend that the proposed White Paper on genomic medicine
(see paragraph 3.12 above) and the Strategic Vision of the Office
for the Strategic Co-ordination of Health Research should identify
barriers to collaborative working between academia and the pharmaceutical
and biotechnology industries, and ways of removing them and also
address the need for incentives for collaboration so as to promote
translational research in the UK.
Assessment, evaluation and regulation
of diagnostic tests
RESEARCH TO DEMONSTRATE THE CLINICAL UTILITY AND
VALIDITY OF GENOMIC TESTS WITHIN THE NHS
3.27. Genetic tests are essential for the diagnosis
of single-gene disorders and genomic tests are becoming increasingly
useful for differentiating treatments of particular groups of
patients in common diseases. The development and assessment of
such tests require research to prove their clinical utility and
validity. But whereas clinical validity is tested as part of any
assessment of the risks and benefits of new diagnostic tests—partly
for funding reasons, clinical utility, which looks at the benefit
to the patient, tends not to be. As a result, there is currently
little data on which to assess the clinical utility of genetic
and genomic tests in the NHS (pp 108, 136-7 and 395). The
Royal College of Pathologists further suggested that research
into clinical utility was inadequate because of "the organisational
difficulty of conducting this type of research; its relative lack
of 'prestige' amongst the scientific community; and a traditional
reluctance of the major grant-giving bodies to fund 'mundane'
research into such practical matters" (p 108).
3.28. Other than tests for single-gene disorders,
genetic tests (such as pharmacogenetic tests and gene expression
profiling) are entering the NHS on an ad hoc basis, often
without a proper assessment of their clinical utility or validity.
As a result, there is a risk that some tests may be used without
good evidence of their clinical utility, and others with clinical
utility may fail to get through the process due to funding difficulties.
Dr Christine Patch, Genetic Counsellor Manager of the Clinical
Genetics Department of Guy's and St Thomas' NHS Foundation Trust,
referred to there being "a sort of technology creep"
and commented that tests were being introduced "prior to
really detailed evaluation". She suggested that these problems
arose because "at the moment there is a funding and policy
gap in that area" (Q 292). The HGC made a similar comment:
"There is a need to assess clinical validity
and utility in specific clinical pathways, as a recent PHG Foundation/Royal
College of Pathologists report has recommended. However, proper
evaluation of clinical utility takes time and may require large-scale
studies; the provision of government funding for this sort of
work would help to ensure that the benefits that could derive
from further development of some types of genetic testing might
be realised" (p 163).
3.29. The IMG also said that, as part of the
assessment of clinical utility and validity, "an individual
accredited service laboratory has to do a considerable amount
of work in, often, completely redesigning an analytical method
used in research to suit it for patient diagnostics. This is a
crucial area of activity for which the NHS makes minimal provision
in support and funding" (p 247). The Joint Committee
on Medical Genetics (JCMG) told us that "the exclusion of
research proposals including novel laboratory testing from the
current funding calls of the NHS National Institute for Health
Research (NIHR) is significantly exacerbating this problem"
of developing such tests, and that other sources of funding were
not bridging the gap (p 550). Dr John Crolla, Chairman
of the JCMG, told us (in June 2008) that the Joint Committee had
tried to have discussions with the NIHR "because several
members have reported that there is a funding gap"—and
the "NIHR would be the place that we would look to create
specific funding streams" (Q 192).
3.30. Although many other funding organisations
cover the assessment of innovations generally (such as the National
Horizon Scanning Centre and the Centre for Evidence-based Purchasing),
none of them have a specific remit to fund development research
into the utility and validity of genomic tests. The Royal College
of Pathologists noted that "all these agencies are selective
in the topics they will address, and many new innovations are
not covered by the remit of any of them" (p 109). Under
the current system, the development of genomic tests is often
funded through the Primary Care Trust itself, through charitable
grants or the MRC, rather than through the NIHR. The arrangements
are informal and usually developed through the interest of individuals
or patient groups. In the view of the IMG, "clear direction
needs to be given that funding for the development of diagnostics
is included in the remit of governmental research-granting bodies"
(p 247).
3.31. Given the evidence we received of a funding
gap, it was in some respects reassuring to hear from the NIHR
Chief Scientific Adviser, Professor Dame Sally Davies (in
January 2009) that NIHR's Health Technology Assessment programme
(HTA) and the Health Services Research Network did have a responsibility
for the assessment of genetic tests and their translation into
clinical practice, and that the DoH were "putting vastly
more money into the Health Technology Assessment programme so
that people can apply for grants to look at … clinical utility"
(Q 858). However, we remain concerned. The HTA programme
does not cover genetic or genomic diagnostic tests alone, but
all diagnostic tests. We are also aware that research proposals
on genomic tests have been declined. The UK Genetic Testing Network
(UKGTN) expressed concern that genetics was not a high enough
priority for research within the HTA, and they noted with disappointment
that the "HTA did not take up a proposal to examine microarrays
and their introduction into clinical practice" (p 212).
3.32. Professor Sir John Bell suggested
that a specific HTA programme for diagnostics was "essential"
as the problems associated with diagnostics were very different
from those associated with therapeutics and "such a programme
would provide information … for the regulatory decision as
to whether or not to license such technologies in the NHS"
(p 226). We agree. We recommend that the National Institute
for Health Research ring-fence funding, through a specific Health
Technology Assessment programme, for research into the clinical
utility and validity of genetic and genomic tests within the NHS.
THE EVALUATION OF CLINICAL UTILITY AND VALIDITY OF
GENOMIC TESTS FOR USE WITHIN THE NHS
3.33. At present, genetic tests for single-gene
disorders which are developed within the NHS are evaluated by
the UKGTN. The UKGTN is a collaborative group of NHS laboratory
scientists, clinical geneticists, NHS commissioners and patient
representatives. Tests that pass the UKGTN evaluation process,
the "Gene Dossier Process", are recommended to commissioners
for funding within the NHS.
3.34. The UKGTN system works well for tests for
single-gene disorders. In contrast, it is unclear how genomic
tests for common diseases, including pharmacogenetic and microarray-based
tests, are evaluated. The Medicines and Healthcare products Regulatory
Agency (MHRA) is responsible for assessing the safety of new "in
vitro diagnostic devices" including genomic tests, but this
task is largely limited to ensuring compliance with EU regulations.
It does not address the clinical validity or utility of tests.
NICE and NHS QIS (Quality Improvement Scotland) have a remit to
evaluate innovations in laboratory diagnostic techniques but in
practice, according to the Royal College of Pathologists, "they
have evaluated only a very small number" (p 109). It
appears, therefore, that there is no body at present with a specific
remit to evaluate pharmacogenetic tests or genomic tests for common
diseases.
3.35. Professor Peter Furness, President
of the Royal College of Pathologists, suggested that the UKGTN
Gene Dossier Process could be adapted to evaluate genetic tests
for multifactorial disorders, but believed that the UKGTN was
"vastly too small" to take on the task of running the
process (Q 193). Professor Sir John Bell took a
similar view: "I am not persuaded that the structure [of
UKGTN] … is necessarily transferable into this rather more
complicated, complex world where clinical utility testing will
have to be done on thousands of patients in large prospective
cohorts" (Q 448).
3.36. The position with regard to the evaluation
of genomic tests contrasts with the evaluation system for new
drugs which, after clinical trials, have to pass through a rigorous
independent evaluation within the National Institute for Health
and Clinical Excellence (NICE) to assess their utility, validity
and cost-effectiveness. According to Roche Applied Sciences,
"the pathway for approval of new drugs in the UK is well-established
…, but there is no NICE equivalent for diagnostics. The lack
of clarity regarding both the regulatory and commissioning pathways
presents a serious barrier to making novel molecular diagnostics
available for clinical evaluation and use" (p 565).
3.37. We note that Lord Darzi of Denham's final
report included a commitment to creating a single evaluation pathway
for new clinical technologies; and we were told by the Minister
for Public Health, Ms Primarolo MP, that the DoH were already
working closely with NICE to develop a new evaluation pathway
which would include genetic testing. She also noted that the Ministerial
Technology Strategy Group was considering the establishment of
a diagnostic evaluation programme, due to start in June 2011 (Q 882).
3.38. We welcome DoH's consideration of a diagnostic
evaluation programme within NICE—but more needs to be done
now. We note Professor Sir John Bell's view that there
is a "need to identify a new agency that can handle the clinical
utility evaluation of diagnostics" and that the NHS should
"utilise NICE for this purpose" (p 226). We agree.
We therefore recommend that the Department of Health extends
the remit of the National Institute for Health and Clinical Excellence
to include a programme for evaluating the validity, utility and
cost-benefits of all new genomic tests for common diseases, including
pharmacogenetic tests.
THE EVALUATION AND REGULATION OF GENETIC AND GENOMIC
TESTS DEVELOPED OUTSIDE OF THE NHS
3.39. Tests are developed both within the NHS
and by independent laboratories (including tests for single-gene
disorders, genetically complex diseases and pharmacogenetic tests).
Those developed by independent laboratories are used within the
NHS, in private healthcare services and directly by the consumer.
Although these tests are regulated through the EU In Vitro Diagnostics
Directive, the Directive does not require their clinical utility
to be proved and nor are they subject to evaluation by an independent
body (Q 299). Under the Directive most genetic tests are
classified as "low risk", which means that the manufacturer
of the test is responsible for ensuring that the test fulfils
the requirements of the Directive rather than a regulatory body
such as NICE or UKGTN.
3.40. Ms Primarolo told us that the MHRA had
acknowledged the concerns raised by Member States, including the
UK, over the classification of genetic tests and that there was
overwhelming support for moving genetic tests to the second highest
risk category. This would require them to be subject to a more
stringent assessment than they are at present. Ms Primarolo told
us: "The Commission are currently assessing the results of
the public consultation and I hope that this will produce some
sort of proposal on the way forward as quickly as possible"
(Q 879).
3.41. We recommend that the Government support
the re-classification of genetic tests to "medium risk"
in the current review of the EU In Vitro Diagnostic Medical Devices
Directive so as to ensure that all genomic tests on the market
have been subject to pre-market review before their use either
by the consumer directly or by the NHS and private healthcare
services.
The development of stratified
or personalised uses of medicines
3.42. Stratified or personalised use of medicines
entails matching therapies to specific patient groups using clinical
biomarkers to target more effective treatments, for example by
taking account of patient susceptibility to particular drugs or
to adverse drug reactions. The stratification of patient groups
for the purposes of prescribing involves using tests—often
genetic tests—to separate patient groups according to their
likely response to a particular therapy. Such tests are required
for certain treatments under NICE guidelines. The number of drugs
for which such tests are recommended is currently small but is
likely to increase in the future. In its 2007 report, Optimizing
stratified medicines, the Academy of Medical Sciences noted
a consensus amongst researchers, economists, healthcare providers
and the pharmaceutical industry that "stratification is desirable
for patients, healthcare systems and companies".
3.43. Stratified use of medicines is the area
of genomic medicine which is predicted to hold the greatest potential
for the healthcare sector in the near-term. It has the potential
to cut the cost of ineffective drug treatments within the NHS
and also reduce life-threatening adverse reactions. However it
also presents one of the biggest translational challenges—not
only because of the complexities of developing and assessing a
medicine and a genetic test at the same time but also because
of the lack of incentives within the pharmaceutical and biotechnology
industries to develop stratified medicines.
3.44. Given that the current blockbuster model
for drug development is not considered to be sustainable in the
longer term and that the industry is under pressure due to the
economic downturn, there is a pressing need for the industry to
develop new business models for personalised medicines and it
is vital to ensure that Government provides industry with incentives
to do so.
INCENTIVES TO DEVELOP STRATIFIED USES OF MEDICINES
Flexible pricing
3.45. At present there is little incentive for
the pharmaceutical industry to develop the genomic tests necessary
for the application of stratified medicines. Under existing business
models for drug development, drugs are targeted at a large number
of patients. This ensures a return on the substantial research
and development investment needed to bring the drugs to market.
But stratified use of medicines is targeted at much smaller patient
groups, and also requires the development of an accompanying test.
For stratified medicines therefore the return on investment and
the cost for treatment will have to be higher for each patient.
3.46. Professor Sir John Bell suggested
that "the delivery of a new set of genetic tools into the
clinic has proved really difficult in every jurisdiction".
One reason for this was that diagnostic companies could not be
relied on "to do what is done in therapeutics, which is to
demonstrate clinical utility" and this was "because
the cost of a clinical utility programme is such that, at the
prices paid for diagnostics, they would never get the money back"
(Q 444).
3.47. Pricing of medicines for use within the
NHS is governed by the Pharmaceutical Price Regulation Scheme
(PPRS). It is a non-contractual scheme aimed at ensuring that
safe and effective medicines are available on reasonable terms
to the NHS, in the context of a strong, efficient and profitable
pharmaceutical industry. Despite this recognition of the needs
of the industry, the pharmaceutical companies, Roche and Astrazeneca,
were critical of PPRS. They told us that it failed to reflect
the therapeutic value of the drugs that companies were supplying
to the NHS (thereby endorsing the findings of an Office of Fair
Trading market study of the PPRS in 2007)—"a situation"
they warned "that is likely to become even more acute as
personalised medicine develops" (p 360).
3.48. Roche suggested that "a new model"
was required "consisting of flexible pricing for personalised
medicines and intellectual property protection and value-based
reimbursement for both targeted drugs and companion diagnostics"
(p 360). This would allow the price of a medicine to be amended
retrospectively if the value of the medicine to patient care had
proved to be higher than first anticipated. In November 2008,
the PPRS was revised to introduce a more flexible pricing scheme
which took into account the possibility of retrospective price
change. According to the report, The Review and Refresh of
Bioscience 2015, this development was welcomed by industry.[13]
3.49. Whilst, as Professor Dame Sally Davies
told us, value-based or flexible pricing was now an option under
the new PPRS and therefore medicines targeted at a stratified
group of patients could be submitted for consideration under the
scheme (Q 906), problems remain. We recommend that the
Government continue to work with the pharmaceutical industry to
extend value-based pricing for the stratified use of medicines
under the PPRS to reflect the value of drugs sold for stratified
use and the increasing use of genetic tests to accompany such
treatments.
3.50. In light of the evidence we received about
existing medicines (Q 719 and pp 360-61), we recommend
further that, with regard to medicines for common diseases which
are already in use in the NHS, the National Institute for Health
Research should target funding to encourage the development of
pharmacogenetic tests to stratify use of these medicines in order
to improve their efficacy and to reduce the frequency of adverse
reactions.
INTELLECTUAL PROPERTY RIGHTS
3.51. Whereas the 2003 Genetics White paper acknowledged
the importance of protection of intellectual property (IP) to
encourage innovation and to ensure that innovations are transferred
into clinical practice, the 2008 Review made no mention of how
IP could be managed in the development of the stratified use of
medicines and their accompanying diagnostics. We are aware that
recent reports on IP—by the Department of Trade and Industry
(DTI) in 2004 and the Gowers Review of Intellectual Property in
2006—concluded that the current law on IP was appropriate,
but we believe that more work needs to be done on the management
of intellectual property rights and the development of stratified
medicines.
3.52. We were told by the UK Intellectual Property
Office (UK IPO) that the 2004 DTI report "supported the view
that the current law and practice in the UK met the needs of researchers"
and that "while the Gowers Review highlighted some historical
concerns about the patenting of genes", it had "indicated
that current policies for the scope of patents in this area were
set at the right level and recommended that these should be maintained"
(p 581). However, the UK IPO noted also that, although the
UK has a strong IP track record in the academic sector, "there
appears to be very little patent filing activity from the hospital
sector", and that "given the importance of clinical
research in developing and understanding disease conditions, it
would be worth considering why this situation arises" (p 592).
3.53. Dr Stuart Hogarth, member of the Society
for Genomics Policy and Population Health, also questioned whether
the current IP arrangements met the needs of researchers involved
in stratified medicines. He told us that "it has been quite
clear in our research [on the regulatory framework for genetic
tests] … that because the industry's traditional business
model is that it has intellectual property in testing platforms,
not in biomarkers, it is poorly incentivised to do clinical studies
that develop the evidence base for the clinical validity"
or utility of new biomarkers. He explained this was because a
company "that puts the investment into such a study",
unless it has intellectual property in the biomarker, "will
immediately have multiple other companies riding on that investment"
(Q 338).
3.54. We recommend that the Department for
Innovation, Universities and Skills[14]
address the issues relating to the management of intellectual
property rights within the healthcare sector to improve incentives
for stratifying uses of new and existing medicines and for development
of pharmacogenetic tests necessary for stratification.
THE CO-DEVELOPMENT AND EVALUATION OF STRATIFIED USES
OF MEDICINES AND GENETIC TESTS
3.55. A further disincentive to the stratified
use of medicines arises from the separate development and authorisation
processes for therapies and diagnostic tests. We received evidence,
for example, that the health technology assessment for new diagnostics
happens too late in the drug development process. According to
the Bioindustry Association (BIA), "it is widely accepted
by drug developers that, as long as the disease and response biomarkers
are known, the earlier they are integrated and analysed in the
clinical development programme, the better. Integration of biomarkers
as early as in Phase I studies gives the opportunity to build
the necessary knowledge to allow personalised medicine to be implemented
at a later stage in clinical practice" (p 487). The
BIA also commented that "timescales for the approval of genetic
tests should not exceed those for drug approval, and medicines
which employ pharmacogenetic information during prescribing must
be assessed in a timely and appropriate manner during reimbursement
decisions by NICE" (p 483).
3.56. The ABPI suggested that "an integrated
regulatory framework for the co-development of a medicine with
a diagnostic or predictive test should be a priority" for
the future. They suggested further that "OSCHR should take
leadership in developing a UK national strategy on stratified
medicines", taking into account "emerging science in
drug discovery and diagnostics; e-Health; clinical application;
regulatory environment; and health economics" (p 368).
The Review and Refresh Bioscience 2015 report also
called for the Government to develop a stratified disease strategy,
involving industry, academia and a wide-range of relevant organisations.[15]
3.57. We share the view that there should be
a national strategy on stratified medicines to promote the development
and use of such medicines. We therefore recommend that the
Department of Health set out a national strategy on stratified
uses of medicines (as part of the proposed White Paper on genomic
medicine recommended in paragraph 3.12 of this report). The purpose
underlying this strategy should be to streamline the co-development
of stratified uses of medicines and of pharmacogenetic (or other)
tests. This should achieve better value for money through
effective targeting of pharmaceuticals by removing the current
barriers to translation and encouraging the development and uptake
of stratified uses of medicines.
Encouraging innovation in the
biotechnology and healthcare sectors
3.58. As we have said (see paragraph 2.5 above)
the UK is well placed to capitalise on the huge potential market
for genomic medicine because of the leading role played by UK
scientists in the field, the availability of charitable and Government
funding, and the ability to conduct genome-related clinical trials
and research within the NHS. However, innovation in the sector
is currently poor, with little uptake by the NHS of innovative
medicines. The BIA told us that "currently the UK is one
of the lowest adopters of innovative medicines in the EU"
(p 486). To address this issue, the ABPI suggested the creation
of an Innovation Platform by the Technology Strategy Board (TSB),[16]
co-sponsored by DoH and DIUS.
3.59. The Minister for Science and Innovation,
Lord Drayson, explained: "The Technology Strategy Board is
the mechanism within Government which identifies those areas where
it is regarded that the UK has strategic competitive advantage
in the scientific area and where there is both significant growth
potential but also meeting what is regarded as the key demand
facing the country" (Q 857). With regard to genomic
science, in particular, he said "as yet the Technology Strategy
Board has not identified genomics as a key platform and it could
be argued that it should, and this is something which I am interested
in looking into." (Q 857). He continued:
"… [genomic medicine is] clearly an
area where the United Kingdom has real global leadership; it is
an area where the United Kingdom also has this unique advantage
of the assets of the NHS and the structures which we have in the
Department of Health. The question is: can we find better ways
to support the development of innovative medicines and wealth
in this country through the exploitation of those assets and that
is certainly something into which I am urging the Technology Strategy
Board to look further" (Q 907).
3.60. We recommend that genomic science is
adopted as a key technology platform by the Technology Strategy
Board, to drive forward commercial development and clinical application
in this area over the next five years and to maintain the UK lead
in genomic medicine.
8 A Report to Government by the Bioscience Innovation
and Growth Team, The Review and Refresh of Bioscience,
January 2009, p 2. Back
9
The 2008 Review, p 26. Back
10
See footnote 8 above, pp 1-2. Back
11
Ibid, p 14 (recommendation 5). Back
12
Natasha Gilbert, "European finding plan 'unviable'",
Nature, vol 456, 4 December 2008, p 551. Back
13
See footnote 8 above, p 4. Back
14
We are aware that on 5 June 2009, after this report was ordered
to be printed by the House, the Department for Innovation, Universities
and Skills (DIUS) and the Department for Business, Enterprise
and Regulatory Reform (BERR) were merged to form the Department
for Business, Innovation and Skills (BIS). Back
15
See footnote 8 above, p 48 (recommendation 15). Back
16
The Technology Strategy Board invests in and manages a range of
delivery mechanisms and programmes to drive technology-enabled
innovation. To guide their work, technology areas are identified,
with Innovation Platforms targeting specific areas of challenge. Back
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