Stratified medicine in the NHS - An assessment of the current landscape and implementation challenges for non-cancer applications
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Stratified medicine
in the NHS
An assessment of the current landscape
and implementation challenges for
non-cancer applications
1
The ABPI represents innovative research-based biopharmaceutical companies, large, medium and small, leading an exciting new era of biosciences in the UK. Our industry, a major contributor to the economy of the UK, brings life-saving and life-enhancing medicines to patients. Our members supply 90 percent of all medicines used by the NHS, and are researching and developing over two-thirds of the current medicines pipeline, ensuring that the UK remains at the forefront of helping patients prevent and overcome diseases. The ABPI is recognised by government as the industry body negotiating on behalf of the branded pharmaceutical industry, for statutory consultation requirements including the pricing scheme for medicines in the UK. The ABPI is grateful to Concentra for its contribution to this work and for developing the report. © 2014 Association of the British Pharmaceutical Industry All rights reserved Printed in the United Kingdom 22
Foreword
Professor Dame Sally Professor Ian Cree,
C Davies, FRS FMedSci FRCPath
Chief Medical Officer and Chief Chair, Interspecialty Committee on
Scientific Adviser Molecular Pathology, RCPath
Research is well underway to develop sophisticated methods for identifying
patient populations who will most likely respond to specific interventions.
Cancer applications have led the way for stratified medicines, with several
stratified cancer medicines in use within the NHS. On the other hand,
particularly for non-cancer applications, there is less clarity around which
stratified medicines are currently being researched and developed and how
they are being deployed in the NHS. This report aims to provide a baseline
understanding of the use of stratified medicines and companion diagnostics in
the NHS.
The UK is committed to being a global leader in the development of stratified
medicines, which will offer significant benefits to the healthcare system and UK
plc. We are uniquely placed to accelerate the application of stratified medicines
because of our academic and industrial research base and the unique potential
of the NHS as not only an engine for research and innovation, but also a leader
in the delivery of that innovation. Ultimately, the use of stratified approaches is
about ensuring that the right patient gets the right treatment at the right time.
The discovery, development and use of stratified medicines requires a balanced
ecosystem based around partnership with many stakeholders including
scientists, clinicians, patients, regulators, the NHS and payers all working
together.
3
Foreword
Stephen Whitehead,
Chief Executive, ABPI
Stratified medicine has real potential This report provides an understanding
to change the way we think about, of the current non-cancer stratified
identify and manage problems with medicine landscape in the NHS. The
our health. The ABPI believes that the knowledge gained from this will help
UK has an exceptional opportunity us all to take the next steps needed to
to realise the benefit of stratified take full advantage of the opportunity
medicine for all stakeholders, not presented by stratified medicine.
least patients.
Progress in stratified medicine has
A stratified approach to medicine been made possible through a strong
has already proven beneficial in the alliance between industry, the NHS,
treatment of a number of cancers, and funders of biomedical science and
researchers are identifying more and the regulator. It is this partnership
more biomarkers that could be used that will continue to provide the
to refine treatments in the future. springboard for further success,
What is less acknowledged is the ensuring full engagement of all parties
rising number of non-cancer stratified dedicated towards a single goal:
applications in development and – improving health outcomes
just as importantly – those which are for patients.
already in use in the NHS, helping to
deliver the right medicine, to the right
patient, right now.
4
5
Contents
Introduction 7
Past and present 10
Promise and benefits 12
Anticipating the future 14
Non-cancer stratified medicine baseline 16
Survey findings 20
Enablers 28
Case studies 30
Research and horizon scanning 33
The economics of molecular testing 34
Lessons learned from cancer stratified medicine 36
ABPI recommendations 38
Conclusion 40
66
Introduction
The ABPI believes that a focus on sparing expense and side effects for those
stratified medicine development,
Background who will not’2. Critically, it also involves
as part of an integrated stakeholder Much of medicine involves the the development, validation and use of
healthcare strategy in the service of stratification of patients into sub-groups companion diagnostics to achieve the
patients, continues to represent a major for diagnosis and treatment. However, the best outcomes in the management of a
opportunity for the UK to demonstrate term ‘stratified medicine’ has evolved to patient’s disease or future prevention.
world-class leadership. mean something more specific, reflecting
A stratified approach has proven
transformation in stratification enabled by
There has been a great deal of anticipation beneficial in a number of cancers and
advances in molecular biology. There are
around the potential benefits of stratified genetic diseases, and researchers are
several variations in definition; the most
medicine. While there have been some working to identify more and more
prominent are outlined in table 1. The
significant success stories in clinical biomarkers that could be used to refine
definitions have in common the notion
practice, these are fewer than would treatments in the future. The ultimate
of tailoring medical treatment to unique,
be expected more than a decade after aim of a stratified approach to medicine
often molecular, characteristics of patients
the completion of the Human Genome is to enable healthcare professionals to
through the use of diagnostics.
Project1. There is a lack of clarity on what provide the ‘right treatment, for the right
stratified medicines are currently being The terms stratified medicine, person, at the right dose, at the right time.’
researched, developed and implemented personalised medicine and precision
Leveraging the continuing scientific
into the NHS, and as cancer applications medicine are often used interchangeably
advances in genomics, molecular biology
have been the exemplar for stratified in the literature. This report uses the
and medical technologies to detect and
medicine, this concern particularly applies simple definition of stratified medicine
classify diseases more objectively lies at
for non-cancer applications. as ‘the tailoring of medical treatment
the heart of stratified medicine. While
to the individual characteristics of each
This report responds to this concern by this report uses the word ‘stratification’ to
patient. It does not literally mean the
building a baseline understanding of the describe this molecular sub-classification
creation of medicines or medical devices
current landscape and provision of non- of disease and disease susceptibility using
that are unique to a patient, but rather
cancer stratified medicine in the NHS. both biomarkers and a description of the
the ability to classify individuals into
phenotype, it is important to note that
stratified subpopulations that differ in
stratification more broadly is not limited
their susceptibility to (or severity of )
to molecular technologies. Advances in
a particular disease or their response
all these areas are leading to an increase
to a specific treatment. Preventive or
in the efficacy and effectiveness of
therapeutic interventions can then be
treatment, including dose selection.
concentrated on those who will benefit,
Table 1: Definitions of stratified medicine
President’s Council of Academy of Medical Sciences Innovate UK (formerly the International Society for
Advisors on Science & Technology Strategy Board) Pharmacoeconomics and
Technology (definition chosen Outcomes Research (ISPOR)
by this paper)
The tailoring of medical treatment Stratified medicine is the Stratified medicine is an effective Stratified/personalised medicine:
to the individual characteristics of grouping of patients based on therapy that requires: use of genetic or other biomarker
each patient. It does not literally risk of disease or response to • A companion diagnostic test information to improve the
mean the creation of medicines therapy by using diagnostic tests • A clearly identified group of safety, effectiveness, and
or medical devices that are or techniques. patients defined by in vitro health outcomes of patients via
unique to a patient, but rather diagnostics, biomarkers, more efficiently targeted risk
the ability to classify individuals defined algorithms, clinical stratification, prevention, and
into subpopulations that differ in responses, imaging, pathology tailored medication and treatment
their susceptibility to a particular • A molecular level management approaches.
disease or their response to a understanding of the disease
specific treatment. Preventive
• Availability of both tests and
or therapeutic interventions can
medicines to clinicians
then be concentrated on those
who will benefit, sparing expense
and side effects for those who
will not.
7
Methodology within clinical practice in the NHS, but was conducted to build a baseline
there is a lack of clarity as to how often understanding of the current landscape
While there are increasing efforts to they are used and where the testing takes and provision of non-cancer stratified
develop the evidence base for stratified place. Access to medicine-diagnostic medicine in the NHS:
medicine, key issues and challenges combinations is also known to vary
exist around its implementation and geographically across the UK.
adoption into routine practice. There
are already established diagnostic tests This report is based on work conducted
throughout 2014. A variety of research
Desk research Desk research was conducted to understand the stratified medicine context and place non-
cancer stratified medicine in the context of biomarker-directed therapies at all stages of
development. More than 30 reports were examined, including:
Interview-based fact finding Interview-based fact finding was conducted through broad engagement with over 30
organisations and 90 individuals throughout the UK, including detailed site visits to the Royal
Liverpool and Broadgreen Hospitals NHS Trust and Imperial College Healthcare NHS Trust. The
interview process sought to develop perspectives of the current non-cancer stratified medicines
landscape from across the local health economy.
Pharmaceutical pipeline survey ABPI member companies were surveyed to develop an understanding of the potential future
demand for biomarker diagnostics required to access stratified therapies.
Professional opinion survey Knowledge gained from the research and interview-based fact finding was used to develop
a national web-based questionnaire to survey professional opinion on non-cancer stratified
medicine and to build a baseline understanding of provision across the country.
The national professional opinion cascaded through many organisations Project participants
survey was designed to develop findings including the National Institute for Health
regarding: Research (NIHR), the National Office for This study directly engaged over 90
Clinical Research Infrastructure (NOCRI), individuals and surveyed over 500
• Interest and awareness individuals from the pharmaceutical
Medical Research Council (MRC),
• Implementation and access Innovate UK (formerly Technology industry, the health sector and academia,
Strategy Board), Academic Health Science and was directed by a steering group
• Perception and expectation of value of ABPI and RCPath members. Their
Networks (AHSNs), the Knowledge
• Implementation challenges Transfer Network (KTN), the Medicine contribution has been invaluable and the
and Healthcare products Regulatory study team would like to thank them for
The survey was launched on 23 July their commitment.
Agency (MHRA), Wellcome Trust, and the
2014. It was distributed to more than
Royal College of Pathologists (RCPath).
500 stratified medicine stakeholders
The survey closed on 10 October 2014
including researchers, commissioners,
with more than 300 completed responses.
providers and industry, and additionally
8
9
Past and present
Hospital in Birmingham showed a more In 1984 planning started for the Human
A brief history definitive response to the medicine at a Genome Project with the goal of
In 1902, Sir Archibald Garrod made higher dose, leading to its approval in the determining the sequence of chemical
the first connection between genetic UK. Since then, tamoxifen’s effectiveness base pairs that make up human DNA,
inheritance and susceptibility to a disease and affordability have earned it a place and of mapping all of the genes of the
– alkaptonuria3. His book, The Incidence on the World Health Organisation’s list human genome from both a physical
of Alkaptonuria: A Study in Chemical of essential medicines for the treatment and functional standpoint. The project
Individuality, is the first published of breast cancer in both developing got underway in 1990 and was declared
account of a case of recessive inheritance and developed countries7. Oestrogen complete in 2003. It remains the world’s
in humans. receptor status can be regarded as the largest collaborative biological project8.
first biomarker to direct a therapy, since
In 1956, the first discovery of a genetic It is perhaps only in the period since
oestrogen receptor positivity determined
basis for selective toxicity was made. the complete sequencing of the human
the use of tamoxifen.
This was for the antimalarial medicine genome in 2003 that the use of stratified
primaquine4. In 1977, the discovery of cytochrome P450 medicine has begun in earnest and is
enzymes and their role in the metabolism now moving beyond the genome into the
In 1971, the first clinical study of an 5
of medicines led to the realisation that entire spectrum of molecular medicine,
anti-oestrogen compound, tamoxifen, in
variation in these enzymes can have a including proteome, transcriptome,
advanced breast cancer took place at the
significant influence on effective dose metabolome and epigenome.
Christie Hospital in Manchester. A second
determination of a medicine.
clinical study6 at the Queen Elizabeth
Recent developments
Launch of the Stratified The National Phenome
Medicine Innovation Centre secures £10
Platform, a five-year million funding from the
programme to accelerate MRC and NIHR for its first
the development and five years. It is the first
uptake of stratified First patients enrolled national level phenome
medicine in the UK. in the Cancer Research centre in the world and will
Encompasses topics The Technology UK Stratified Medicine deliver access to a
such as improved tumour Strategy Board (now Programme, a world-class capability in
The ABPI launches profiling and treatment in known as Innovate UK) partnership with UK metabolic phenotyping
Stratifying Disease for cancer, accelerating the begins funding Government and industry able to handle around
Personalised Medicine identification, validation industry-led consortia to to develop a tumour 100,000 samples per year.
white paper, a platform and adoption of support profiling database and The centre takes advantage MRC and Wellcome
requested by the biomarkers, and the commercialisation of explore how multi-gene of the legacy 2012 Trust will fund detailed
Technology Strategy uptake of medicine and products and services in panel tests could be Olympic state-of-the-art imaging assesments of
Board (now known as companion diagnostics the field of stratified used routinely within drug testing/analytical up to 100,000 UK
Innovate UK) in the NHS medicine the NHS laboratory Biobank participants
2009 2010 2011 2012 2013 2014
UK Biobank recruits The UK LIfe Science Following initial funding MRC funds new Announcement of a new Innovate UK (formerly
participants aged 40-69 Strategy incudes of £62m, and a further disease-focused vision for the UK to be a known as the
to provide samples to investment of £130 £25m secured until stratified medicines global leader in genomic Technology Strategy
improve our million to support the 2016, the UK Biobank collaboration in medicine, with plans to Board) launches the
understanding of a range discovery, development opens for research, partnership with industry invest £100 million to Precision Medicine
of serious illnesses - and commercialisation of offering access to a in rheumatoid arthritis pump-prime whole Catapult focused on the
including heart diseases, stratified medicines unique dataset and and diabetes genome sequencing of commercialisation of
stroke, diabetes, arthritis, samples from 5,000,000 up to 100,000 patients, diagnostic tests (whether
cancer, osteoporosis, adults across the UK starting in cancer and in vitro, imaging or
depression and forms of rare diseases otherwise) designed for
dementia use in precision
(stratified) medicine, with
9
the goal of making the
UK the leading place
worldwide to develop
and launch new
diagnostic tests in
this field
10There has been a dramatic increase in the amount of research in this area.
Publication keyword search results: 1983 - 2014
6,000
5,000 Precision medicine
Stratified medicine
4,000
Personalised medicine
Publications
3,000
2,000
1,000
0
83
86
88
90
92
94
96
98
00
02
04
06
08
10
12
14
19
19
19
19
19
19
19
19
20
20
20
20
20
20
20
20
A publication keyword search10 was conducted to establish the number of academic
articles containing the term ‘stratified medicine’, ‘personalised medicine’, or
‘precision medicine’ over the past 30 years using PubMed (a searchable database of
more than 24 million citations for biomedical literature).
Note: Searches were conducted using the US spelling (‘personalized’) as well as the
UK spelling (‘personalised’) to reflect the international publication landscape.
Stratified medicine vs. personalised medicine as a keyword search term:
2001 - 2014
100%
80%
Proportion of total
60%
40%
20%
0%
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Stratified medicine
Personalised medicine
The search term ‘stratified medicine’ returned the majority of search results in 2001.
Since 2010 ‘personalised medicine’ has grown to account for the majority, indicating
the trend towards increasingly accurate stratification to smaller sub-groups11.
Note: Searches were conducted using the US spelling (‘personalized’) as well as the
UK spelling (‘personalised’) to reflect the international publication landscape
11Promise and benefits
• Non-cancer example: Familial and Vectibix (panitumumab) because
The promise of stratified Hypercholesteroaemia is an inherited their tumors have a mutated form of
medicine condition that causes significant the KRAS gene 14.
elevations of plasma cholesterol
Stratified medicine has the potential to • Non-cancer example: Abacavir
and increased risk of cardiovascular
change the way we think about, identify is a nucleoside analogue reverse
disease. Mutations in three key
and manage health problems. It is already transcriptase inhibitor (NRTI)
genes have been associated with
having an exciting impact on both clinical used to treat HIV and AIDS. The
predisposition to elevated cholesterol
research and patient care, and this impact main undesirable effect of Abacavir
levels. Diagnosis can lead to early
will grow as technologies improve. is hypersensitivity, which in rare
intervention with cholesterol
cases can be fatal. A genetic test can
Stratified medicine promises three key lowering treatment, which effectively
indicate a patient’s predisposition to
benefits: lowers cholesterol concentrations
hypersensitivity, therefore avoiding
and can substantially reduce the risk
1 Better diagnosis and earlier adverse events by pursuing alternative
of cardiovascular disease. However, it
intervention. Molecular analysis could therapeutic options.
is estimated that only 15% of affected
determine precisely which sub-phenotype
individuals are clinically diagnosed in 3 More efficient medicine development.
of a disease a person has, or whether they
the UK. A better understanding of genetic
are susceptible to medicine toxicities,
variations could help scientists identify
to help guide treatment choices. For 2 Optimal treatment selection. Currently,
new disease sub-groups and their
preventive medicine, such analysis could an empirical approach is used to find
associated molecular pathways, and
improve the ability to identify which the most effective medication for each
design medicines that target them.
individuals are predisposed to develop a patient. As we learn more about which
Molecular analysis could also help select
particular condition, and guide decisions molecular variations best predict how
patients for inclusion in, or exclusion
about interventions that might prevent it, a patient will respond to a treatment
from, late stage clinical trials — helping
delay onset or reduce impact. This offers and develop accurate and cost-effective
gain approval for medicines that might
the opportunity to focus on prevention tests, doctors will have more information
otherwise be abandoned because they
and early intervention rather than on to guide their decision about which
appear to be ineffective in a larger, more
reaction at advanced stages of disease. medications are likely to work best. In
heterogeneous patient population.
addition, testing could help predict the
“Diseases are more easily prevented than
best dosing schedule or combination of • Cancer example: A predictive
cured and the first step to their prevention
medicines for a particular patient. Many biomarker for Iressa (Gefitinib) was
is the discovery of their exciting causes.” –
patients do not benefit from the first discovered approximately seven years
William Farr 12
medicine they are offered as treatment. after the start of clinical trials. It then
• Cancer example: Women with The use of genetic and other forms of took another four and a half years of
certain BRCA1 or BRCA2 gene molecular screening allows doctors to retrospective research to demonstrate
variations have an increased lifetime select an optimal therapy first time and to significant increase in clinical
chance of developing breast cancer avoid the frustrating and costly practice of benefit for those patients identified
or ovarian cancer compared with trial-and-error prescribing. by the diagnostic test. Ultimately,
the general female population13. the discovery of the biomarker has
• Cancer example: Genetic testing can
The BRCA1 and BRCA2 genetic enabled the identification of patients
be used to evaluate which medicines
test can guide preventive measures, most likely to benefit and offers
may be the best (or worst) candidates
such as increased frequency of an alternative treatment option to
for treating colon cancer. For example,
mammography, prophylactic surgery doublet chemotherapy in newly
approximately 40% of patients with
and chemoprevention. diagnosed advanced/metastatic non-
metastatic colon cancer are unlikely
small cell lung cancer.
to respond to Erbitux (cetuximab)
Patients can respond differently to the Percentage of the patient population for which a
same medicine, and many patients do particular drug in a class is ineffective, on average
not benefit from the first drug they
are offered in treatment. For example,
approximately half of patients do not Anti-depressants (SSRIs) 38% 62%
respond to first line arthritis therapy16. Asthma drugs 40% 60%
The use of genetic and other forms of
molecular screening allows doctors to Diabetes drugs 43% 75%
select an optimal therapy, thus avoiding
the time-consuming and costly Arthritis drugs 50% 50%
practice of trial-and-error prescribing.
Alzheimer’s drugs 70% 30%
Cancer drugs 75% 25%
Effective Ineffective
12• Non-cancer example: Cystic fibrosis chloride, weight gain, improvement Potential benefits to
(CF) is a life-limiting, multisystem in patient-reported quality of life, and
disease caused by loss or dysfunction reduction in number of respiratory stratified medicine
of the CFTR protein. Improved exacerbations in clinical trials. stakeholders
understanding of CFTR protein Although Ivacaftor is currently only
dysfunction has allowed the licensed for use in approximately 5% The stratified medicine ecosystem
development of mutation-specific, of the CF population (those who have a covers stakeholders from across the
small-molecule compounds that specific mutation), the developmental industry, including payers, providers,
directly target the underlying CFTR pathway could pave the way for other pharmaceutical companies, diagnostic
defect15. Ivacaftor is the first licensed CFTR modulators that may benefit companies, regulators and of course
small-molecule compound for CF more patients in future. patients. Stratified medicine offers
patients and has the potential to different benefit potential to each, as
be truly disease-modifying; having shown in this diagram:
shown benefit in terms of an increase
in lung function, decreased sweat
Stakeholder benefits of stratified medicine
• Safer, more effective medicines
• Focused discovery and development programmes based on more refined disease diagnosis
• Improved descision making and potentially lower attrition
• In the longer term, the ability to develop individual medicines with a greater value proposition with
regulation and study design keeping pace (caveat: the costs of clinical trials are likely to go up in the
near term with additional cost of development and validation of biomarkers required as diagnostics, and
inability to pre-specify target populations accurately without a large number of patients)
• Earlier approval of new therapies with improved confidence in post-marketing pharmacovigilance systems
• More accurate targeting of the marketing of medicines
• Increased differentiation of new therapies from generic therapies leading to more valued patients
thus greater likelihood to adhere to treatment
• More cost effective healthcare Pharmaceutical • Improved healthcare due to better
resources due to: Industry matching of patients needs and
- Improved response rates for the therapeutic benefit
treatment of diseases • Reduced liklehood of adverse events,
- Avoidance of side effects and and thus greater incentive to remain on
Payers and Patients
increased use of effective treatments therapy (especially for pre-morbid
Providers conditions such as hypertension and
- Avoidance of treatment for those hypercholesterolaemia)
who don’t need it, or won’t benefit
from it Stratified • More informed choice of therapy
• More rapid access to new and innovative
• Improved and more specific diagnosis
of diseases and their prognosis leading
Medicine medicines that work for patients
to more accurate forecasting on • Access to broader range of therapies
healthcare resource requirements. supported by the NHS
Regulators Diagnostic
Industry • Greater personal involvement in
treatment descisions and thus greater
likelihood to adhere to treatment
• Greater confidence for earlier/conditional approval and thus earlier • Increased opportunity for cost effective diagnostics to partner with
access for patients the currently approved medicines and medicines in development,
• Greater confidence in the interpretability of pharmacovigilance data opening up new collaborative space with academia, patient groups,
healthcare systems, pharmacuetical industry and government
17
13Anticipating the future
The advent of next generation sequencing
Falling cost of obtaining technologies has dramatically decreased
Increasing clinical value of
molecular information the cost per MB of DNA sequence. molecular information
Between January and October 2008 the
The pace of technological change As the cost of obtaining and storing
cost dropped from £63 to £2.40 – today it
has dramatically reduced the cost of molecular information has fallen, the
is approaching 50p per MB. Similarly, data
obtaining molecular information. The clinical value of molecular information
storage costs have dropped dramatically:
Human Genome Project gave us the has also increased substantially as
1GB of storage cost £121,000 in 1980, this
first complete sequence of the human an increasing number of molecular
was down to £6.00 in 2000, and today it is
genome - it cost about $3 billion and biomarkers have been found to have
in the region of 3p.
took more than ten years to complete. clinical validity.
Since then, the introduction of next The cost of acquiring specific diagnostic
The value of molecular information
generation sequencers has seen the cost information continues to fall as test
increases as new applications are
of sequencing an entire human genome technology improves. The current trend
clinically validated for existing biomarkers
plummet from approximately £60,000 in towards panel testing – which conducts
and as new biomarkers become clinically
2000 to less than £3,000 today. multiple molecular investigations
validated. In short, the more clinically
simultaneously – is replacing individual
As both the cost and time involved valid uses we find for molecular
tests due to its ability to deliver a lower
continue to reduce, it may soon be biomarkers, the more valuable this
unit cost per investigation.
possible to sequence genomes in hours for information becomes.
less than £1,00018.
The cost per MB of DNA sequence
reduced from £63 in January 2008 to
£2.40 in October of the same year. Today
it is approaching 50p per MB. 1GB
of data storage cost
£121,000 in 1980, by
Falling fast 2000 this was down
In the first few years after the end of the Human Genome Project, the cost of genome
to £6.00, and today
sequencing roughly followed Moore’s Law, which predicts exponential declines in it is in the region
computing costs. After 2007, sequencing costs dropped precipitously. of 3p
100,000
Moore’s
Law for c
omputing
costs
10,000 Cost of genome
sequencing
Next generation
Costs (US$ 1,000)
10,000 sequencers enter
the market
The price of sequencing
a whole human genome
100 hovers around $5,000
and is expected to drop
even lower
10
1
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
14FDA drug approvals requiring an associated biomarker
1949 - 2013 (cumulative total)
140
The number
120 of Food and Drug
Administration (FDA)
medicine approvals
100
containing an associated
biomarker has increased seven-
80 fold since 1993, an average
annual growth rate of
60 17%
40
20
0
49
59
69
79
89
99
09
13
19
19
19
19
19
19
20
20
How big is the big • Facebook stores 600 Terabytes (TB)
of data every day. If the UK were to
data challenge?
UK At the most basic level, each DNA base
accumulate genomic data at the same
rate, we would have genomic data on the
genomic data pair requires 2 bits of digital storage. Since
there are about 2.9 billion base pairs in the
entire population after 75 days.
Today retrieval, not storage, is the main
= human genome, (2 * 2.9 billion) bits ~= 691
Megabytes (MB). In reality, slightly more
issue. Clinicians need to make time-
sensitive decisions. Making use of this
75 days of than 2 bits are required since a ‘storage
overhead’ is created by other bases in
vast amount of data takes time and is
not easily made available at the point of
Facebook sequence information. As a result, the
amount of raw storage has been estimated
care. The challenge is how to analyse,
synthesise and package the information
data at 750-770 MB. in a way that is useful for healthcare
To put this in context: professionals – when they need it.
• The hard disk on a typical PC can store
500 Gigabytes (GB) of data (equivalent to
500,000 MB). This is enough to store the
full genome for more than 650 people.
• To store genomic data for the entire
population of the UK would require
just over 46 million GB, or 46 Petabytes
(PB) of storage. It may sound a lot,
but this is only 15% of the size of the
data warehouse that Facebook uses,
which holds some 300 PB of digital
information. Google processes this
amount of data every two to three days.
15Non-cancer stratified medicine baseline
optimal treatment selection, and more in stratified medicine. There are currently
Current landscape efficient treatment development. The over 200 biomarker-directed therapies at
As previously mentioned, stratified pharmaceutical industry’s focus on all stages of development19.
medicine promises three key benefits: products associated with biomarkers
better diagnoses and earlier interventions, summarises the industry’s perceived value
Pharmaceutical products associated to biomarkers (Phases I - IV)
Antineoplastic and immunomodulating agents 79
Nervous system 40
Alimentary tract and metabolism 17
Cardiovascular system 15
Respiratory system 12
Musculo-skeletal system 12
Various 11
Antiinfectives for systemic use 9
Dermatologicals 5
Genito-urinary system and sex hormones 4
Sensory organs 3
Hormonal preparations for systemic use 2
Blood and blood forming organs 2
Cancer applications have led the way cancer applications20. However, less- medicine applications at all stages of
for stratified medicine, and near-term reported and less-discussed are the development. Engagement throughout
stratified medicine development and growing number of non-cancer stratified the stratified medicine community
implementation efforts continue to focus medicine applications in development revealed an additional 36 non-cancer
on cancer: an assessment of 30 stratified and being used in practice. At the outset stratified medicine applications for a total
therapies currently in pharmaceutical of this report engagement within the of 41 applications of non-cancer stratified
pipelines revealed that 27 (90%) were ABPI revealed five non-cancer stratified medicine as shown in table 2.
Non-cancer stratified medicine applications provided by interviewees
Infection 15
Respiratory 6
Cardiovascular 5
Familial genetic disorders 4
Renal 3
Neurology 3
Transplantation 2
Diabetes 2
Rheumatology 1
16Significant effort was required to ‘all medicine involves stratification of
discover each of these 41 applications patients’; others considered a diagnostic
of non-cancer stratified medicine.
Interviews were conducted across
test as a necessary component of a
stratified application; some stressed a
Few
a range of therapeutic areas. Some molecular-level diagnostic and therapy as interviewees
interviewees stated that stratified a necessary requirement for labelling an
medicine was ‘not here yet’ for their application as stratified. used the same
given area; others listed a handful of
applications in research or practice; many
Equally challenging was determination definition of
added the caveat that these were ‘low
of the NHS status of many of the
non-cancer applications. Of the 41
stratified medicine
volume’ or ‘very rare’. Researchers and
practitioners were generally only aware
applications discovered, interviewees in identifying
knowledgeable about each application
of applications in their clinical area or
listed 13 as ‘available’ in NHS pathways, applications
sub-speciality; few had cross-speciality
12 as ‘required’ in NHS pathways, and
knowledge of applications, and additional
seven as still ‘in research’. Interviewees
research revealed no single database
were unaware of the NHS status for the
or consolidated perspective on non-
final nine applications. This unawareness
cancer stratified medicine applications,
of NHS status underscores a more general
development status, availability or use.
finding: there was a lack of awareness
Few interviewees used the same and agreement amongst practitioners as
definition of stratified medicine in to the availability of most applications
identifying applications. Some noted that within the NHS.
Looking forward Results showed an expected 27% year- on the market, which are also expected
on-year growth in demand from new to increase diagnostic test volume as
It is expected that stratified medicine will applications for stratifying diagnostics equality of access expands. It is unknown
continue to grow in applications and in use. through 2018. 27 of the 30 stratified whether all of these pipeline therapies
This perspective was substantiated through therapies were in cancer applications, will reach market and be used within
a therapy-associated diagnostic demand further substantiating the expectation that the NHS. It is also unknown how many
survey sent to all ABPI member companies, cancer applications continue to be a key additional medicine-diagnostic therapies
which consolidated the expected future area of development focus21. are in pharmaceutical pipelines and the
demand for stratifying diagnostics associated incremental diagnostic test
associated with 30 stratified therapies It should be noted that this perspective
volume should these reach market, though
currently in development pipelines. only considers new medicine-diagnostic
an upward trend is expected.
combinations. It does not consider
demand uplift from therapies currently
Estimated incremental diagnostic test volume based on current development pipelines21
Compound
annual
growth rate 162,020
27%
Head and neck cancer
122,020
Ovarian cancer
Colorectal cancer
90,520
Melanoma
63,020 65,020
Breast cancer
Lung cancer
Leukaemia
Asthma
2014 2015 2016 2017 2018
17Table 2: 41 non-cancer stratified medicine applications and information
provided by interviewees
No. Application Area Indication Diagnostic Test Application Associated Reported NHS
Therapy(s) Status
1 Cardiovascular Familial LDLR, PCSK9, ApoB Screening, Statin Available
Hypercholesterolemia mutations diagnosis
2 Cardiovascular Heart Failure ST2 protein, BNPS Screening - Available
3 Cardiovascular Ischemic heart disease Coronary artery calcium Diagnosis - Required
(IHD) score
4 Cardiovascular Anticoagulation CYP2C9/VKORC1 Dosing Warfarin In Research
5 Cardiovascular Stroke / DVT Cytochome P450 Dosing Clopidogrel Available
6 Diabetes Monogenetic neonatal HNF1A - Sulphonylureas Available
diabetes
7 Diabetes Maturity onset HNF1A - Sulphonylureas Available
diabetes of the young
8 Familial Genetic Factor V Leiden Factor 5 leiden mutation Screening - Required
Disorders thrombophilia testing
9 Familial Genetic Cystic Fibrosis G551D mutation in CTFR - Ivacaftor Required
Disorders gene
10 Familial Genetic Cystic Fibrosis G551D mutation in CTFR - Lumacaftor In Research
Disorders gene
11 Familial Genetic Cystic Fibrosis m1555a Screening - Required
Disorders
12 Infection Measles Measles PCR Test Diagnosis - Unknown
13 Infection Meningococcal Meningococcus PCR Test Diagnosis - Unknown
disease
14 Infection Pneumococcal Pneumococcus PCR Test Diagnosis - Unknown
diseases
15 Infection Chlamydia Chlamydia PCR Test Screening - Unknown
16 Infection Hepatitis C Hep C PCR Test Diagnosis - Required
17 Infection Tuberculosis TB Sequencing Diagnosis - In Research
18 Infection HIV HLA-B*57:01 Screening Abacavir Required
19 Infection Fungal infections CYP2C19 Dosing Voriconazole Available
20 Infection HIV Tropism assay Selection Maraviroc Available
21 Infection HPV HPV screening Screening - Available
22 Infection Diarrhoea (e.g. Diarrhoeal panels Diagnosis, - Unknown
congenital chloride Therapy selection
diarrhoea)
23 Infection Multiple indications G6PD Screening Aprimoquin Required
(antimalarial)
Rasbiracase
(antigout)
24 Infection HIV CD4 Screening Nevirapine Available
25 Infection HIV Creatine clearance Screening Tenofavir Available
26 Infection HIV 516GT - Efavirenz Required
27 Neurology Epilepsy HLA-B*1502 Neurology Carbamazepine Required
18No. Application Area Indication Diagnostic Test Application Associated Reported NHS
Therapy(s) Status
28 Neurology Epilepsy, Alzheimer’s, PET scan Diagnosis, - Available
Parkinson’s and other Therapy selection
neurological disorders
29 Neurology Suspected stroke CT / MRI imaging Diagnosis, Thrombolytic Required
Therapy selection therapy if no
haemorrhage
30 Renal IgA nephropathy Molecular analysis - - Unknown
31 Renal atypical Haemolytic Molecular analysis - - Unknown
Uremic Syndrome
(aHUS)
32 Renal C3 glomerulopathy Molecular analysis - - Unknown
33 Respiratory Asthma IL5 assay - Unknown
34 Respiratory Asthma Serum periostin levels Therapy selection Anti-IL13 In Research
therapies,
including
Lebrikizumab
35 Respiratory Asthma, White Blood Eosinophil counts Therapy selection Mepolizumab In Research
Cell diseases
36 Respiratory Asthma Eosinophil counts Therapy selection Benralizumab In Research
37 Respiratory Primary Ciliary Molecular analysis Diagnosis - In Research
Dyskinesia
38 Respiratory Interstitial Lung Molecular analysis Screening - Available
Disease
39 Rheumatology IgG4-RD Molecular analysis Diagnosis - Required
40 Transplantation Autoimmune, TPMT Screening Azathioprine Required
Transplant
41 Transplantation Seropositivity - - Ritumimab Available
(RF and anti-CCP)
19Survey findings
As previously mentioned, knowledge Respondents reported professional
acquired through desk research and
Participants interest across a wide range of application
interview-based fact finding was used Data from over 300 survey respondents areas including infection, respiratory,
to develop a web-based survey of was analysed. Respondents covered a cardiovascular, familial genetics, renal,
professional opinion on non-cancer range of professional backgrounds, and neurology, diabetes, transplantation
stratified medicine. The survey was were geographically located across a and rheumatology.
designed to develop findings regarding: representative sample of regions.
• Interest and awareness
• Implementation and access
Respondents’ professional background (n = 331)
• Perception and expectation of value Clinician 158
• Implementation challenges Laboratory professional 105
Other 28
Researcher 24
Pharmaceutical company 12
Commissioner - national 2
Diagnostic company 2
Respondents’ geographic location Respondents’ professional
(n = 290) interests vs. non-cancer stratified
medicine applications
Infection
Respiratory
30
Cardiovascular
Familial genetic
disorders
5
33 Renal
24
Neurology
Transplantation
51
14 Diabetes
39
Rheumatology
62
32
0% 10% 20% 30% 40%
Applications
Professional interests
20Interest and awareness Awareness of uses and applications of stratified
Respondents were generally interested medicine in the NHS (n = 233)
in non-cancer stratified medicine: 61%
Expert 10%
reported ‘high’ interest in emerging uses,
applications and impacts of non-cancer High 20%
stratified medicine, with additional 33%
reporting ‘moderate’ interest. Though highly Medium 35%
interested, they were most likely to report a
‘medium’ personal level of awareness of the Low 24%
uses and applications of stratified medicine
in their professional area(s) within the None 11%
NHS. These findings were consistent across
surveyed regions and professions.
“In a senior position
in particular it’s key
to keep as up to date as
possible.”
61%
of respondents report a high
“Not all clinicians are aware interest in emerging uses
of the opportunities.” of non-cancer stratified
- Survey Respondents medicines
21Implementation and access To what extent are stratified medicines implemented in
Only 8% of respondents thought that the NHS? (n = 181)
stratified medicines could be considered
‘widely implemented’ in the NHS. Widely implemented 8%
There was little regional variation in the
distribution of responses to this question, Partially implemented 43%
although respondents from Wales and
the Midlands were slightly more likely to Sparsely implemented 31%
find that stratified medicines had not been
implemented in the NHS. Overall these Not implemented 18%
findings suggest that non-cancer stratified
medicine implementation can be improved
system wide. Regional distribution of implementation (n = 181)
Correspondingly, about 25% of
respondents said that there was ‘good Not implemented
access’ to stratified medicines, while 30%
Sparsely implemented
indicated that there was ‘poor access’.
Following the findings regarding NHS Partially implemented
implementation, the regional differences
among the responses were limited, though Widely implemented
Scotland and the North East of England
reported slightly higher access levels.
“Across the UK it is
very variable with no clear
guidance on the best
testing strategy.”
“Routes to funding lab tests
is a constant issue.”
“The big issue is the clinically
actionable result and the diagnostic
support for it.”
- Survey Respondents
How would you rate the level of access to non-cancer
stratified medicines in your area? (n = 173)
25% Good access
45% Some access
30% Poor access
22Perception and 86% of respondents indicated that they Although there is strong positive
expect the value of stratified medicine sentiment, some have been surprised that
expectation of value to increase in the next four years; 13% there haven’t been more positive outputs
90% of respondents expect non-cancer thought it would be roughly the same. from stratified medicine thus far. 97%
stratified medicine to have a positive The remaining 1% (two respondents) of respondents believe the NHS is not
impact on the health system in the UK. anticipated the value from non-cancer currently maximising the potential value
Eight percent of respondents expect stratified medicines would actually from non-cancer stratified medicine, with
non-cancer stratified medicine to decrease, citing the high cost of treatment 40% of respondents claiming the NHS is
have a neutral impact. Two percent of as a barrier. One respondent specifically ‘achieving little’ or ‘no benefit’ from non-
respondents expect a mildly detrimental expressed doubt that the NHS would ever cancer stratified medicine.
impact; these respondents were laboratory pay for the diagnostics required to access
professionals who cited the overwhelming stratified therapies.
cost of stratified medicines as the reason
for the mildly detrimental impact.
Do you expect stratified medicine to have a positive
“Over the next 20 years impact on the health system in the UK? (n = 167)
I believe that [stratified
medicine] will transform the Yes
treatment of cancer, inflammatory
and autoimmune disease.”
54% significantly
positive
“[Stratified medicine is] probably the
most important change in the practice
of medicine in the next 20 years.” Yes
- Survey Respondents
36% mildly
positive
8% Neutral
2% No mildly
detrimental
To what extent do you believe that the NHS is maximising
the potential value from stratified medicine? (n = 162)
40% Maximising potential
Achieving some but not all benefits
3%
57%
of respondents claim the NHS Achieving little benefits 36%
is achieving little or no benefit
from non-cancer stratified No benefit at all 4%
medicine.
23In addition to general questions on For several of these tests respondents Of those that claimed to be sure, a
perception and expectation of value, disagreed on test availability. Some consensus regarding availability was
respondents were questioned on respondents claimed that they had used reached on only 13 of the 41 tests.
applications in their declared therapeutic these tests while others claimed they
Respondents were also asked to list what
area(s) (e.g. cardiovascular, infection). were not available. This wide variability
drives the value of the most beneficial
Respondents were asked to list their areas of knowledge as to test availability was
test in their area of interest. Across all
of interest and provided a list of non- pervasive throughout the 41 stratified
disciplines, most respondents listed
cancer stratified medicine application medicine applications listed in the
‘increases the predictive value of the
within these areas. They were also asked survey. On average, about half of the
therapeutic outcome’ and ‘gives patients
to select the test that would provide the respondents for any given test were ‘not
access to treatments they otherwise would
most benefit to the health system. sure’ if it was available in the NHS.
not have had’ as the top choices.
Top application values across all professional areas (n = 152)
It increases the predictive value of
33%
the therapeutic outcome
It give patients access to treatments they
32%
otherwise would not have had
It enables us to avoid treating patients who
20%
will have a negative adverse event
It enables patients to get access
11%
to treatment faster
It decreases the cost of medicines by
4%
making the trial process more efficient
Top application values, distribution across professional areas
It increases the predictive value
of the therapeutic outcome 24% 14% 22% 22% 10% 6%
It gives the patient access to treatments
they otherwise would not have 16% 6% 20% 20% 6% 12% 6% 8%
It enables us to avoid treating patients
who will have a negative adverse event 7% 7% 10% 27% 10% 7% 33%
It enables patients to get access to treatment faster 6% 6% 12% 35% 24% 6% 12%
It decreases the cost of medicines by
making the trial process more efficient 17% 17% 17% 17% 17% 17%
Cardiovascular Diabetes Familial Glucocorticoid Deficiency Infection
Neurology Renal Respiratory Rheumatology Transplant
24Implementation challenges Is access restricted due to one or more of the following?
There is a high degree of alignment (n = 137)
concerning implementation challenges.
98% of respondents agreed that there are
significant challenges to implementing Availability of companion
56%
stratified medicine in the NHS, with 90% diagnostic tests
claiming that the health system will have to Funding for companion
change to support the adoption of stratified 30%
diagnostic tests
medicine. There was broad agreement that
treatment complexity and volumes of data Availability of treatments 9%
will increase with implementation of non-
cancer stratified medicine. Funding for treatments 5%
The widest barriers to access were
analysed by asking respondents to select
reasons stratified medicines may not be
accessible in the NHS. More concern
was expressed for diagnostic testing for
stratified medicines rather than for actual
stratified treatments. One provider focused
on diagnostics as the key to unlocking value “A good diagnostic
from therapies, stating that, ‘We have the network with reflex
therapies. The challenge is that we don’t testing of all relevant
“Scientific evidence
know how to apply them.’ These findings molecular markers is
available, translation not
were consistent across surveyed regions needed and this requires
always possible due
and professions. a proper funding system
either to lack of funding
in parallel.”
Both availability and funding of such or clinical
diagnostic tests were listed as access understanding.”
restrictions more frequently than
availability and funding for stratified
medicine treatments combined. This
was further corroborated by responses
to the question ‘What is needed to “Lack of NHS
IT integration “Communication
achieve full implementation of stratified and interaction
and absence of
medicine?’ The top two responses were between disciplines is
bioinformatics
both related to diagnostic testing as part required. More
skills.”
of a treatment pathway. The top item was collaboration is
‘reimbursement and access to diagnostics required to develop a
and medicines’ which 133 respondents comprehensive
agreed was needed. The second most diagnostic network.”
frequently cited item was ‘medicine and
diagnostic research and development,’
which 90 respondents agreed was needed. “Simplification
needed – route to
testing can be too
“There is a need
complex in
for more research
particular.”
on cost effective
implementation
and making tests “Good information
“There will be huge available.” networks required to
amounts of data obtain outcome data.
especially as sequencing This should be through
and variant analysis the NCIN in Oxford and
becomes more “Significant data submission should
widespread. I am not challenges include be a prerequisite for
sure the UK has the technology, reimbursement.”
network capacity to deal funding, expertise,
with this presently. Do pressure from
we need an information patients, etc.”
highway like USA?”
Survey respondents
25What is needed to achieve full implementation of stratified medicine? (n = 157)
Reimbursement and access to diagnostic and drugs 133
Medicine and diagnostic R&D 90
Funding 81
Education 42
Better guidelines 36
Better communication and collaboration 33
Quicker test results 26
Human resources 12
Better regulation 3
Access to information on non-cancer
stratified medicines, especially from
Information about stratified medicines is...(n = 245)
the NHS itself, was frequently cited as
‘difficult’ or ‘somewhat difficult’ to obtain.
Only 5% of respondents thought that
information was widely available. Sources 19% Difficult to obtain
that respondents listed as containing
information regarding stratified medicines
were journal articles and studies, NICE
guidance, and pharmaceutical conference
proceedings. Several respondents said
32% Somewhat difficult
to obtain
that while information existed it was not
convenient to find or use. These findings
were consistent across all professional
backgrounds.
44% Somewhat available
Respondents also provided their
perspective on the data challenge. They
pointed to data interpretation as the
biggest challenge in non-cancer stratified
medicine. They further listed a lack of 5% Widely available
data to support clinical decision making
as another major challenge, indicating
a strong interest in connecting data to
practical results.
What is the biggest data challenge in stratified
Despite these challenges, there is no doubt
about the future. Stratified medicine
medicine? (n=160)
is working its way into the NHS, it is
Interpretation of data
providing value, and this value will grow. 42%
generated by tests
Lack of data to support
29%
clinical decision making
Lack of tests in
13%
certain indications
Lack of data supporting
10%
use of tests
Sensitivity/specificity of data 6%
2627
Enablers
Enabling better communication and collaboration: The National Pathology
Exchange22 (NPEx)
The National Pathology Exchange With NPEx, laboratory managers can see focal point for procurement and clinical
(NPEx) is a national service for NHS which laboratories offer which tests for expertise.
pathology managers to connect UK what price and can review turnaround
The cost of the NHS managing lab-to-lab
laboratories together through a single and performance. Request details are
referrals by paper was estimated at
exchange hub so that test requests and sent electronically from the sending
£2million a year in 2001. Since then
pathology results are sent digitally from laboratory system to the receiving
lab-to-lab volumes have increased
lab-to-lab. The system is designed to laboratory system and, once the tests are
significantly, partly due to growth
replace an estimated six million pieces of complete, the results are immediately
in demand for more testing but also
paper which are currently sent between transmitted back.
as a deliberate network strategy, a
NHS laboratories and being manually
Once a laboratory is connected to NPEx recommendation from the Carter Report
input into computer systems, taking an
it can drive out major inefficiencies by (2006, 2008)24. The volume of lab-to-
estimated 300 man years of effort and
outsourcing those tests which can be lab communications will continue to
leading to a significant clinical risk from
done cheaper elsewhere, while retaining grow with the consolidation of specialist
human input errors and two days delay
flexibility and capacity to respond to services, the rapid growth in point of
for patients getting results23.
local demand. NPEx will help pathology care testing and the opening up of the
departments to ensure they remain a marketplace for laboratory services.
Picking
Request list and delivery Samples Bar code
details notes printed from sent confirms sample Request
transmitted to NPEx arrives details transmitted
Sending LIMS to receiving LIMS
Test
requested on
hospital or GP
order ComsSystem Test performed
Results
received
immediately Results
confirmed
Results
sent immediately
Benefits:
• Helps deliver faster service to patients • Reduced opportunity for errors • Could help break down the
and clinicians introduced during data entry organisational and geographical
barriers to collaboration
• Estimated cost savings £1-3 per sample • Auditable sample trail – bar-coding
– data entry, handling, postal and paper used from end-to-end • Roll-out of the NPEx system to date
has been regional.
• At least one day faster service as results • Reduces ad-hoc enquiries as electronic
received electronically and not by post status checking and monitoring
• View of market intelligence supports
better commissioning decisions
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