Licensed to Cure?
Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness
appraisals of licensed medicines
Summary
• Approaches which undervalue new treatments can impede innovation, distort therapeutic
decision making and undermine global welfare. This report considers the public policy
implications of the use of unlicensed, low cost, comparators in appraisals of the cost
effectiveness of new (and repositioned) medicines by health technology assessment
(HTA) agencies such as NICE. It also critically examines other aspects of current health
technology evaluation methods which threaten incremental innovation and discourage
‘high risk’ research investment.
• At the ‘coal face’ of health care there are strong pressures to use the cheapest version
of any medicine thought to be more or less equivalent to more expensive presentations,
regardless of whether or not it is licensed for the indication concerned. When people are
facing life threatening conditions there are also occasions when they legitimately wish to try
unlicensed medicines. However, the rigorous safety testing and drug licensing requirements
that have been developed since the thalidomide tragedy exist to protect the public’s interests
in medicines development and their appropriate use. They should not be bypassed simply
to save money.
• European law requires that medicines licensed for the condition being treated should be
used whenever possible. Unlicensed medicines use is legitimate only when it is likely to
give a patient extra clinical benefit. In such circumstances prescribers ought to inform
patients of their situation, and must accept personal legal liability for their actions. No form
of unlicensed prescribing can be justified on grounds of cost saving alone.
c
This report was researched and written by David Taylor, Tina Craig and Jennifer Gill. It was commissioned
by the European Medicines Group (EMG), which has 17 research-based European pharmaceutical sector
company members. EMG members Bayer and Novartis provided the majority of the funding to support the
development of the publication. The research methods used were determined by the authors and editorial
control was exercised by Professor Taylor, who is accountable for all aspects of this document’s content.
c
• NICE has many positive achievements to its credit. Neither its demands for the use of
unlicensed medicines as comparators in cost effectiveness analyses (which may make new
medicines seem unaffordable) nor its implicit and explicit recommendations to prescribe
treatments for unlicensed indications in areas like, say, the care of teenagers with severe
mental illness are likely to have significantly harmed public health. Yet they challenge the
integrity of medicines licensing, and may threaten overall public interests in sustained
innovation. Continuing NHS ‘austerity’ and an increased emphasis on saving cash could
lead to more serious future problems stemming from the use of unlicensed comparators,
unless abuses are checked. NICE should not become a serial instigator of new forms of
unlicensed medicines use.
• In the short term a more precise definition of what is considered ‘established health service
practice’ could help avoid such problems. Ideally, independent policy makers will prevent
NICE from requesting the use of unlicensed comparators in cost effectiveness analyses, or
from (implicitly or explicitly) recommending unlicensed medicines prescribing when licensed
options exist. NICE is no longer an NHS authority. It would therefore also be appropriate
for it to be required to take full account of the benefits of biopharmaceutical and other
innovations to the whole of society, not just isolated health technology users or NHS budget
holders.
• In cancer care, some NICE judgements seem out of line with expressed public preferences.
Major ‘intangible’ costs in terms of reduced NHS user confidence in their ability to access
good care may have resulted. In England (but not Wales) the Cancer Drug Fund currently
facilitates the supply of anti-cancer medicines judged non-cost effective by NICE. In
Scotland different cost-effectiveness conclusions have often been drawn. Such phenomena
– together with other ‘rare disease’ linked concerns – raise questions as to the validity
of the ‘cost per incremental QALY’ and relatively narrowly defined affordability threshold
based methodology currently used by NICE, over and above those related to the use of
unlicensed and other arguably unsuitable ‘commodity cost’ comparators in ‘value based’
innovation assessments.
• Recent changes to the Pharmaceutical Price Regulation Scheme, which cap total NHS
medicines spending regardless of the total volume and mix of products used, also suggest
a need for modifications in NICE’s approaches to restricting therapeutic choice. The
variable ‘marginal’ costs of manufacturing safe and effective medicines are typically small
compared with those ‘sunk’ before they are marketed. Investors in high risk medicines
research need confidence in their ability to fund what might appear small incremental
advances, but which in the long term are integral parts of a process that should lead to
transformative human benefit. If HTAs fail to reflect the full current and probable future
social and economic benefits of biopharmaceutical and associated medical innovation they
could in the final analysis impose costs which far outweigh the short term, local rather than
national, monetary savings they may generate.
2
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
Introduction
Since the end of the 1940s world-wide average
life expectancy at birth has risen from under 50 to
approaching 70 years. This for each person on the
planet represents a gain of three additional years for
every decade lived. Much of this historically unique
progress can be attributed to falling infant and child
mortality in poorer countries. Yet it is also the case that
in richer settings men and women who survive childhood
can now expect to live to over 80 years. Around a half of
this improvement has been due to modern health care
developments and improved health in later adult life.
Key drivers include the contributions of medicines and
vaccines in protecting populations against infections and
reducing the risks of dying from events such as strokes
or myocardial infarctions.
In age standardised terms, cancer death rates are now
starting to fall in the more prosperous nations (Stuart
and Wild, 2014). In addition to reducing mortality,
modern pharmaceuticals are also playing important
roles – alongside other forms of medical innovation
and social and economic progress – in reducing the
disabling impacts of ‘non-communicable’ (albeit often
socially mediated) illnesses ranging from depression and
Parkinson’s disease through to diabetes and asthma.
Yet notwithstanding their value to humanity, the safety of
modern medicines has throughout the last century been
a matter of recurrent public concern.
Thalidomide was developed in West Germany and
initially marketed there in 1957 as Contergan. It quickly
became seen as a ‘safe’ alternative to barbiturate use
(Emanual et al, 2012). By 1960 it was in widespread
use outside the US, and was available for purchase in
Germany without medical prescription. Yet when about a
year later its teratogenic (embryo and foetus damaging)
effects had been identified and the product withdrawn
in Germany and later elsewhere, some 10,000 infants
with significant physical disabilities had been born. An
uncertain, probably greater, number of foetuses had in
addition died before birth.
The thalidomide tragedy, which was followed by the
practolol1 ‘scandal’ of the 1970s (see Abraham and
Davis, 2006) and subsequent concerns about the on
some occasions fatal consequences of taking the nonsteroidal anti-inflammatory drug benoxaprofen (Opren),
led on over the course of the last few decades to an
international tightening of pharmaceutical licensing
requirements. The idea of achieving absolute safety in
any area of human activity can be a potentially harmful
chimera. But regulatory progress has helped to protect
1 A beta blocker most widely known as Eraldin. Medicines in this
class have generated large benefits, albeit that practolol – which
is chemically very similar to drugs such as propanolol – was
uniquely associated with a destructive form of conjunctivitis and
other unwanted side effects. Benoxaprofen was an effective antiinflammatory agent (Dawson, 2014). But it caused problems such
as skin hyper-sensitivity to light and liver damage in older patients
with an impaired ability to clear the drug. It was not tested in this
last patient group before marketing because at that time neither
regulations nor established practices demanded it.
the global public from avoidable harm caused by
inadequately tested medicines. In the United States, for
example, where the Food and Drug Administration (the
US FDA) had developed a relatively robust approach
to medicines licensing before the start of World War
II, the 1962 Kefauver-Harris Amendment introduced
new requirements for both unwanted event reporting
and evidence of efficacy before the granting of a new
marketing authorisation – Box 1.
In the UK the Committee on Safety of Drugs, a forerunner
of today’s Medicines and Healthcare Products Regulatory
Agency (MHRA), was established in 1963. Some 30
years later, in 1995, the European Medicines Evaluation
Agency (now the European Medicines Agency) came
into being. There remain areas of controversy relating to,
for instance, the publication of unsuccessful trial results.2
But in general such developments have been associated
with the evolution of a licensing system and wider set of
controls which effectively prevent new medicines being
marketed for indications that have not been approved
by public agencies charged with balancing their potential
risks against their demonstrable benefits.
In the US, pharmaceutical companies have since 2000
been fined a cumulative total over $10 billion, for in part
promoting medicines for unauthorised uses. These
in some circumstances (such as neurological pain
management and in a proportion of diabetes cases)
have ultimately been proven beneficial to patients. Yet
in others more harm than good may have been caused.
The legal and public interest arguments surrounding
such issues are more complex and finely balanced than
is often assumed. Nevertheless, such high profile legal
actions and penalties illustrate how much the regulatory
control of the pharmaceutical market has tightened over
the course of the last 50 years.
Alongside the evolution of progressively more rigorous
marketing authorisation systems for medicines, a
number of other fundamental pharmaceutical sector
changes have recently occurred. One has been the
establishment in Europe of bodies such as IQWiG (the
German Institute for Quality and Efficiency in Health
Care) and the French HAS (the Haute Autorité de
Santé/National Authority for Health). Like NICE (now
2 Over 30 years ago Skegg and Doll (1977) argued in favour of
recording all adverse events (rather than just those immediately
attributable to the treatments being tested) and reporting them
to central agencies during clinical trials. They correctly believed
this would have permitted the early identification of practolol’s
ocular toxicity. More recently, some observers have claimed that
the open publication of all successful and unsuccessful clinical
trial results would prevent large numbers of avoidable deaths
(Goldacre, 2012). Others argue that this is an exaggeration
(Johnston et al, 2013). Provided the trials used to justify licensing
and recommended clinical practice demonstrate with robust
statistical validity safe and productive ways of using given
products, then it is reasonable to suggest that the value of
publishing material relating to their unsuccessful application is
likely to be only marginal. In some circumstances it could prove
confusing. However, this does not apply when knowledge of
the outcomes of failed approaches could protect against further
hazardous experimentation, or help better inform off-label/
unlicensed prescribing. Minimising the need for the latter is
one way forward. But obligatory reporting of all adverse events
occurring during clinical trials to responsible central agencies is
also needed.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
3
Box 1 The origins of modern pharmaceutical sector regulation
In the late 1930s American attempts to produce the
German and French pioneered antibiotic sulphanilamide
led to the sale of an elixir (mixture) containing diethylene
glycol, a sweet tasting but toxic solvent more
appropriately used in anti-freeze products. It killed
about a hundred people. The consequent public and
medical outrage led in 1938 to the passing of the Food,
Drug and Cosmetics (FDC) Act. This strengthened
the FDA and demanded pre-market safety testing by
drug manufacturers. The FDCA put the US regulatory
approach ahead of Europe’s controls on medicines
safety. Progress with the latter was in part delayed
by the impacts of the 1914-18 and 1939-46 wars. In
addition, European pharmaceutical sector was more
capable than its American equivalent and so not so
clearly in need of extended regulation.
However, despite this action another 300 deaths
occurred in the US in 1941 because of the sale of
another early antibiotic, sulfathiazole. Some batches
of this medicine were adulterated with a barbiturate
sedative in sufficient quantities to suppress respiration.
This manufacturing error led the FDA to introduce
pioneering production quality checks. These overtime
evolved into today’s Good Manufacturing Practice
(GMP) standards.
the National Institute for Health and Care Excellence) in
England and Wales and the Swedish Council on Health
Technology Assessment (the SBU), these organisations
are concerned with promoting the cost effective use of
medicines and other health technologies. As such their
interventions can complement, and also on occasions
challenge, those of pharmaceutical licensing (and also
purchasing) authorities.
Other, more fundamental, shifts have taken place in
relation to the research challenges facing pharmaceutical
innovators in both the public and private sectors.
The main focus of their work can be seen as having
moved from seeking small molecule ‘chemistry based’
treatments for common diseases to developing relatively
large molecule ‘biologicals’ that target specific (and
often comparatively rare) mechanisms underpinning
given disease processes. At the same time there have
also been reforms in areas such as the reimbursement
systems used to determine payments for publicly
purchased pharmaceuticals. In the UK, for instance,
recently announced amendments to the Pharmaceutical
Price Regulation Scheme (the PPRS) will serve to cap
overall NHS spending on medicines. This should in the
main ensure that over a given consumption level the
marginal public cost of any drug supplied via the health
service is, whatever its apparent price, in effect zero.
Against this background, the primary goal of this UCL
School of Pharmacy report is to consider the public
policy implications of the use of unlicensed (typically
relatively low cost) comparators in appraisals of the cost
effectiveness of newly licensed medicines by government
4
In the 70 years following these ground breaking
interventions similar forms of safety and quality related
regulation have been introduced on a global scale,
although not before events similar to the elixir of
sulphanilamide disaster had occurred on a larger scale
in countries such as India and Nigeria. As described
in the main text, the thalidomide tragedy also served
to extend drug safety legislation. Today, all aspects
of pharmaceutical industry activity, from research to
marketing, are subject to extensive scrutiny and control
in all OECD nations. This is increasingly so in emergent
nations as well, as recent events in China illustrate.
The establishment of NICE in 1999 can be seen
as a further important step forward in the history of
pharmaceutical and wider health sector regulation.
However, earlier safety and quality interventions were
aimed at protecting individual patients. By contrast, the
pursuit of increased cost effectiveness is in a number
of important respects more relevant to protecting
taxpayers’ interests and population health. ‘Products’
such as NICE guidelines can also challenge medical
authority and judgements, rather than just directing
pharmaceutical producers’ and suppliers’ activities in
contexts such as pricing and marketing.
funded or other health technology assessment agencies.
It begins with a brief overview of the key issues at stake,
and the particular economic nature of medicines and of
pharmaceutical innovation and supply. The advantages
and drawbacks of activities such as what is popularly
termed ‘off-label’ prescribing (the use by doctors of
licensed medicines for purposes which have not been
authorised by regulators) and ‘compassionate’ drug
provision (the regulator permitted supply and use by
doctors of entirely unlicensed treatments for the care of
patients with special needs, such as individuals whose
lives are threatened by currently incurable diseases) are
also analysed.
This study then considers data relating to the use by
NICE of unlicensed comparators in single technology
appraisals (STAs) undertaken in the period between 2008
and 2013. Alongside this, and in the light of a series of
ten qualitative interviews with stakeholders undertaken at
the end of 2013 and in early 2014, it considers questions
such as the extent to which such practices represent an
endorsement of the use of unlicensed products for cost
cutting as opposed to health improvement purposes.
As and when cost saving (even when illusory, because of
factors such as PPRS variables) is the primary reason for
using medicines for unlicensed indications the legality of
the latter is doubtful throughout the European Union. So
is its wider social desirability from a long term health care
improvement perspective. The degree to which harm to
public and professional interests in safe and appropriate
pharmaceutical care delivery has so far been caused in
Britain or elsewhere as a result of such practices (which
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
can stem from clashes between regulators seeking to
promote drug safety and ongoing therapeutic innovation
on the one hand, and agencies pursuing financial
efficiency on the other) should not be exaggerated. There
is little or no evidence of significant direct health impacts
to date, albeit effects such as a reduced trust in the
NHS are hard to monitor. However, in future – especially
if research costs continue to rise while health services
come under increasing financial pressure – more serious
consequences could arise.
In such circumstances it will be increasingly important for
policy makers, together with groups such as patients’
representatives, to recognise the value associated with
the use of appropriately licensed medicines whenever
these are available. At the same time they should seek a
sympathetic understanding of the pressures on day-today service providers who are trying to optimise service
efficiency and health outcomes despite what are often
perceived to be increasing budgetary restraints. To
people working at the ‘coal face’ of health care it may
seem only common sense to use a cheaper version of a
medicine rather than a similar but more expensive one.
Communicating why this is not necessarily in the public’s
interest is a difficult challenge. Yet it is not one that should
be avoided by any individual or agency that is seeking
to maximise global social returns and to promote better
health in the longer term.
Defining the issues
Clashes between patient and public interests in providing
robust incentives for innovation in the future as against
maximising treatment affordability in the present can be
illustrated in contexts such as that preventing sight loss
caused by ‘wet’ age related macular degeneration – see
Box 2. In this atypical instance significant health gains
have been associated with the successful introduction
of ranibizumab (Lucentis), a ‘humanised’ monoclonal
antibody fragment which inhibits the effects of vascular
endothelial growth factor (VEGF). When injected into the
Box 2 Macular degeneration
Age-related macular degeneration (AMD) is a type
of retinal damage that results in loss of sight in the
macula, the 2 per cent or so of the eye’s light sensitive
inner surface responsible for central vision. It occurs
in both ‘dry’ (non-exudative) and ‘wet’ disease forms,
normally in people aged over 50. Although peripheral
vision is retained, untreated wet macular degeneration
(which is associated with a destructive proliferation of
blood vessels in the affected part of the retina) is a
common and distressing cause of partial blindness.
There are in the order of 25,000 new UK cases
annually. Fortunately, modern medicine can transform
the outlook for people with AMD and other retinal
disorders. But they need to be able to access effective
and appropriately delivered treatment in a timely and
affordable manner.
eye in small amounts (0.5 milligram doses) on a once
a month basis for an initial three months (subsequent
treatment needs vary) it prevents the abnormal growth
of blood vessels characteristic of this common cause of
sight loss.
However, this medicine has to date (during its period
of intellectual property protection) been relatively costly,
typically involving NHS outlays of about £10,000 per eye
treatment (NICE, 2008). (For reference, this is broadly
comparable to the overall cost of an NHS hip replacement
operation – Pennington et al, 2013.) A desire to minimise
costs has on occasions led to aggressive rationing being
proposed. In addition to denying some older people
access, suggestions have in the past included providing
patients with treatment in one eye only after central
vision has been lost in the other. Late stage mono-ocular
treatment does not maximise the benefits potentially
available, and is not today NHS policy or practice.
Bevacizumab, a much larger ‘anti-VEGF’ molecule to
which ranibizumab is related, is marketed as Avastin
for the treatment, in combination with other drugs, of
a number of cancers.3 Used in higher and much longer
lasting systemic doses, bevacizumab benefits patients
by stopping tumours stimulating the formation of new
blood vessels that they need to sustain their growth. This
medicine is also generally regarded as a costly product.
Yet the fact that it is employed in relatively large amounts
(which on a monthly basis are up to 1000 times greater
than the dose needed for a single eye injection) to treat
oncology patients in part explains why its price per
milligram is only 5-10 per cent of that of ranibizumab.
There are expenses and some risks involved in breaking
vials of bevacizumab formulated for intravenous injection
and re-presenting their contents for unlicensed optical
use. Nevertheless, the price difference that exists has led
to calls for ‘cheap’ bevacizumab to be supplied in place
of the licensed drug for the treatment of retinal disease.
Given the pressures on health service resources in
Europe and elsewhere, such thinking is understandable.
But the issues involved are complex. In relation to the
savings possible, for instance, it is commonly assumed
that if a manufacturer of bevacizumab were in future to
to obtain a licence for a presentation for treating retinal
disorders it would be automatically supplied as a low
unit dose cost alternative treatment for AMD and other
indications such as Diabetic Macular Oedema (DMO).
However, commercial logic suggests that a producer
enjoying intellectual property rights might not in fact
adopt such a strategy, and opt for a price close to that
of existing treatments.
More detailed aspects of this unique debate are not
relevant to the subject of this paper, and there are in any
3 Bevacizumab is also ‘humanised’ in that a murine (mouse) antibody
is ‘encased’ in human proteins. But some of its properties differ
markedly from those of ranibizumab. For example, the systemic half
life of the former is only about two hours, while that of bevacuzimab
is twenty days. This difference is related to that fact that bevacuzimab
was designed to treat cancers, while ranibizumab was structured
to have an optimal effect within the environment of the eye while
carrying a minimal risk of causing unwanted vascular or other events.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
5
Box 3 Medicines re-purposing
The terms drug re-purposing and medicines
repositioning both refer to identifying and developing
new uses for existing drugs (Ashburn and Thor,
2004). Because virtually all pharmacologically active
agents have a number of potentially useful therapeutic
applications this may be a valuable activity in areas
ranging from cancer care (Gupta et al, 2013) through
to cardiovascular disease prevention (Russell, 2011).
Nevertheless, gaining new indications for ‘mature’
molecules in a financially as well as clinically viable
manner can present innovators with a number of
significant challenges (Novac, 2013).
However, in both these cases the drugs in question were
not being marketed immediately before the change in
use. Achieving such a switch while a low cost generic
version is commonly available, as might be the case if
for instance an innovator were to seek to licence a new
indication for a drug such as a bisphosphonate, would
be very much more difficult. This is in part because
professionals such as pharmacists and doctors might
elect to supply the low cost product for the new use,
and in part because agencies like NICE might also
employ the generic version as a comparator in cost
effectiveness studies.
One well known example of repositioning is that
of thalidomide. This drug is today marketed under
the trade name Thalomid and used to treat multiple
myeloma, as well as for the relief of complications
resulting from leprosy. Another successful illustration of
re-purposing is that of buproprion. Originally developed
as an anti-depressant, it is now marketed under the
brand name Wellbutrin for the support of smoking
cessation (Boguski et al, 2009).
In such circumstances innovators would be unlikely to
be able to offer the new presentation at a financially
viable price, given the challenges and risks involved
in developing established drugs for new therapeutic
applications. For example, contrary to what is
occasionally suggested, primary safety trials need to be
repeated when agents are employed in ‘fresh’ disease
contexts.
case further innovations being developed which will limit
its future significance. One new treatment, aflibercept
(Eylea), has already been licensed. But this unusual case
highlights the fact that medicines with similar or even
identical active ingredients can be very differently priced.
The various reasons for this appear legitimate to their
producers and (at least in principle) to public agencies
seeking to maximise safety and incentivise the research
needed for continued innovation and evidence based
indication licensing. Yet major price variations can seem
exploitive to other observers.
With regard to the future use of unlicensed comparators
in health technology appraisals, tensions and disputes
are particularly likely to occur in instances where older
mature medicines are re-purposed for new indications
(Box 3). They may also occur when new molecular
entities are developed and licensed for use in contexts
where established generic products can subsequently
be shown to work with varying degrees of positive effect.
The economics of pharmaceutical research
and production
Understanding why innovative medicines (which for
the purposes of this analysis can be taken to include
both new medicinal/molecular entities and treatments
containing mature active ingredients that have been
re-formulated and licensed for new indications) may be
priced at levels much higher than those at which similar
generic medicines can be obtained requires insight into
the economics of pharmaceutical research investment
and licensed drug manufacturing. A key point to stress is
that in the case of traditional ‘chemistry based’ medicines
the marginal costs of their production are typically very
low compared to the amounts of money sunk in their
6
research and development, including the clinical trials
now required across the world.
Biological products such as monoclonal antibodies
are inherently more difficult to produce to a consistent
standard. Yet even so, their average supply cost during
the period of exclusive supply awarded by governments
to innovators to encourage further investment in high risk
research is likely to be multiples of the marginal cost of
their production. This is especially so when innovation
costs are taken to include not only the outlays made on
discovering, testing and marketing successful medicines,
but also the resources spent on the numerous drug
candidates that fail along the development pathway.
When new medicines are said to on average cost £1
billion or more to develop, such figures include failure
costs as well as those of the ‘risk capital’ needed to
sustain prolonged research programmes.
The pricing of new medicines is inherently controversial,
not least because of the uncertainties involved in
attempting to answer questions such as ‘what
proportion of its resources should a society invest in
research on innovations for the future as opposed to
current consumption?’ and ‘what level of anticipated
premium do private investors need to induce them to
risk spending in areas where research is more likely to
fail than to lead to a marketable medicine?’ (LundebyGrepstad et al, 2014). There are also important but
frequently ignored issues to be considered with regard
to the balance between the pricing of pharmaceutical
innovations and the duration of the intellectual property
rights4 available to innovators, and the extent to which
in environments like that of the EU and the US public
4 IPRs include patents, periods of regulatory data exclusivity,
copyrights, brand names and trademarks.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
investments in fundamental and translational research on
medicines and other therapeutic innovations are driven
by long term expectations of private sector income
generation.5
For example, extended pharmaceutical IPR durations
could permit reduced entry prices for new products,
albeit that this would be against the interests of
generic medicine producers and in some (but not all)
circumstances the potential users of low cost unbranded
drugs. Likewise, although professional and public
opinion may sometimes assume that public investment
in areas related to the development of new treatments
would be likely to increase if private sector research
and development were to decline, it appears that the
two tend to be positively correlated. This implies that
private R&D investment falls could in time be followed
by reduced rather than increased public spending on
University and other publicly supported biomedical and
related research.
This topic is not pursued further here. But with regard to
the use of unlicensed comparators in cost effectiveness
appraisals the most important point to stress is that the
economics of pharmaceutical research and production
mean that the cost per dose of an unbranded generic
version of a medicine sold for established uses is always
likely to be much lower than that of the same or a new
molecular entity that has been formulated and licensed
for use for a new indication, at least during the limited
period during which IPRs apply.
Unlike rare substances such as gold, the value of any
new medicine lies essentially in the knowledge and
cognitive skills that permit its use in ways that cause more
benefit than harm, rather than in the physical materials of
which it is made. If agencies responsible for HTAs and
the measurement of ‘cost effectiveness’ were to fail to
adequately recognise this reality they could undermine
the structures needed to support ongoing innovation. In
such circumstances short term savings would be gained
at the expense of very much greater long term societal
costs.
‘Off-label’ prescribing
In popular usage the term ‘off-label’ prescribing denotes,
as previously observed, the use by doctors of licensed
medicines for unlicensed purposes. It is therefore in
legal terms a subset of unlicensed drug prescribing,
albeit ‘off-label’ prescribing is – rightly or wrongly –
often taken to have less hazardous connotations. In the
past pharmaceutical companies have sometimes been
accused of stimulating ‘off-label’ product use in order,
with or without good clinical reason, to increase sales
levels. But the prescribing of medicines for unlicensed
indications is important in the context of this UCL School
of Pharmacy analysis because it is through the direct or
5 Governments can tax their domestic populations to fund home
expenditures on politically viable activities such as University
based fundamental research. But they are often dependent
on privately owned or at least semi-privatised ‘arms length’
enterprises for foreign earnings generation, and for supporting
activities that are necessary but politically ‘risky’.
indirect encouragement of such drug use that some
health care funders may today be seeking to reduce
pharmaceutical costs.
When the US FDA was first established in 1906 it was
against the background of a still unsophisticated and
often corrupted pharmaceutical sector. In the nineteenth
century practicing pharmacists in America generally
lacked the education and expertise of their counterparts
in European countries like Germany, France and
Britain. Regulation was also minimal. The term ‘snake
oil salesmen’ originally referred to the often fraudulent
makers and purveyors of ‘patent’ medicines. These
often modified versions of traditional herbal treatments
frequently contained ingredients such as morphine,
cocaine and alcohol. Beyond the immediate relief of pain
and distress they on many occasions did more harm
than good (Thum Bonnano et al, 2012).
The American medical profession, by contrast, had
already achieved a relatively high level of public trust and
social standing by the start of the 1900s. The pioneering
legislation facilitating the formation and subsequent
development of the FDA was therefore framed in a way
that made it clear that it was not intended to interfere
in doctors’ treatments of ‘their’ patients. It was focused
rather on regulating the manufacturing and supply of
medicines. Despite modern challenges to concepts such
as ‘clinical freedom’ and the emergence of hierarchical
control systems within and around the medical profession
in the UK and other settings, the intention of controlling
drug quality and the behaviours of drug makers and
vendors without impinging on informed medical practice
has lived on for over a century in the US and globally.
The continued existence of ‘off-label’ prescribing should
be understood in this light, and the fact that until the last
two to three decades much medicines use developed
incrementally. That is, product prescribing patterns
evolved ‘on the market’. When a medicine had been
authorised for use for one purpose it was often regarded
as ‘safe’ in an absolute sense. This explains why ‘offlabel’ prescribing is frequently taken to be less risky
than using drugs which have no licensed indications
whatsoever. Hence it is the term preferred by advocates
of unlicensed drug applications.
Traditionally, once a first drug use was registered this
allowed other usages to be established informally, by
‘trial and (on occasions continued) error’. One contributor
to the research undertaken for this report likened the
process to a rock being thrown into a pool, with an
increasing number of ‘drug use ripples’ spreading out
over the surface of established practice after the initial
splash of a new marketing authorisation.
The medically sanctioned supply of drugs for unlicensed
indications continues to be widespread in fields
ranging from paediatric medicine to pain management,
psychiatric care and cancer treatment (Box 4). The
inherent complexities of health care, coupled with factors
such as ongoing discoveries about how to employ
treatments to best effect and individual patient variations
in need and response, help explain why this is so.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
7
As a result, few commentators say that there is no
justifiable place for off-label prescribing in medical practice
– see, for example, Figure 1. The licensed indications for
a medicine are not necessarily its most desirable ones,
particularly when considered from any one individual’s
perspective (Healy and Nutt, 1998; Sugarman et al,
2013). However, there are concerns that the use of
medicines for unlicensed purposes on occasions not
only lacks an evidence base, but sometimes appears to
be actively hazardous and unlikely to confer net benefit
on consumers.
The inappropriate use of anti-psychotics in the care of
people with dementia falls into this latter category. In
addition, there are uncertainties and variations relating
to issues such as the extent to which physicians
in the UK and elsewhere in the EU are legally liable
for misadventures which may happen as a result of
unlicensed drug usage. Problems are particularly likely
to occur when doctors have either not informed patients
Figure 1: Patient group views on ‘off-label’
prescribing
• 64% of patient groups across Europe believe that off-label prescription is
valuable and legitimate when patients with life-threatening conditions have
no other therapy available to them.
• 63% of patient groups across Europe believe that off-label prescription is
valuable and legitimate for patients (such as children, or people with rare
diseases) who have only limited treatments available to them.
Percentage
of respondent
patient groups
commenting
on whether the
prescription
of off-label
medication is
valuable for
patients
64%
63%
28%
27%
7%
10%
As a last resort, when patients
with life-threatening conditions
have no other therapy available
to them
For patients (such as children,
or people with rare diseases)
who have only limited treatments
available to them
Yes, this is legitimate and valuable for patients No, it is not I do not know
Source: Irish Patients Association, 2012
Note: The IPA surveyed 150 European Patient Groups
Box 4 The extent of unlicensed medicines prescribing
Unlicensed medicines prescribing involving licensed
drugs employed for ‘off-label’ applications is on
occasions a result of historical lags. Sometimes drugs
have been in common usage for so long that extended
uses have emerged ‘naturally’, without any individual
or agency having a viable opportunity (or sufficient
motivation) to organise and fund formal authorisation
for all the indications for which it is in practice used.
Tricyclic antidepressants, for instance, have long been
widely employed as not only a therapy for depression
but also for treating conditions ranging from irritable
bowel syndrome to neuropathic pain. Although now
often seen as being too hazardous for ‘every-day’
licensed use in mental health care, such medicines
are nevertheless widely valued as a low cost agent in
the treatment of neuropathic pain. However, despite
NICE’s recognition of this established practice (NICE,
2013), it is an unlicensed application. This opens up the
possibility that were harm to befall a patient – and had
the practitioner involved not explained the situation to
the individual in his or her care – they might be subject
to legal or professional action, albeit in this instance an
effective defence might be available unless additional
poor practice issues were to be involved.
Typically, unlicensed prescribing has been most
frequently found in fields where those in need of
treatment have therapeutic requirements which differ
from those of the mainstream adult population, and/
or where current remedies prove inadequate. Relevant
areas include paediatric medicine (see, for instance,
Hill, 2005), psychiatry (Baldwin and Kosky, 2007; Haw
and Stubbs, 2007) and the care of people with life
threatening illnesses such as cancers. Logically, it is in
this last context where the pressure for access to as yet
entirely unlicensed treatments is likely to be greatest –
see main text.
8
The available evidence indicates that the majority of
doctors have prescribed licensed drugs for unlicensed
indications. In some instances such behaviour is
commonplace. For example, one survey of the ‘offlabel’ use of mood stabilisers in a large psychiatric
hospital found that of 250 patients studied in a given
period 30 per cent were receiving such medicines,
95 per cent of which were being used for unlicensed
purposes (Haw and Stubbs, 2005). In other contexts
observed rates of unlicensed medicines prescribing
are much lower, but are nevertheless significant and in
some instances concerning.
A relatively recent study of GP’s attitudes towards and
experiences of prescribing for children (whose physical
immaturity means that they frequently require atypical
drug doses and presentations) found that 40 per cent
had knowingly used medicines ‘off-label’ (Elkins-Daukes,
2005). Other research undertaken in Germany found
that parents frequently have a poor understanding of
this area. On questioning, about one in five of those with
healthy children and one in ten of those with a child with
a long term illness said they would always reject the use
of an unlicensed medicine, were they informed about its
prescription (Lenk et al, 2009).
In the last five to ten years unlicensed medicines prescribing
rates may have decreased, except in oncology. Further,
the scale of the harm caused by unlicensed medicines use
relative to the benefits generated via clinicians exercising
informed personal judgement in the care of patients
should not be overstated. Yet there is nevertheless a
need for caution, especially when vulnerable service users
are involved or where prescribers are under pressure to
save money. In general, increasing the percentage of
pharmaceutical products supplied for licensed indications
is a desirable goal, provided it is pursued in ways which
consistently put patient wellbeing first.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
that they are prescribing ‘off-label’, or have failed to
obtain an adequate record of consent to treatment.
At the regional and international policy levels there are
also as yet unresolved questions as to the extent to which
it is (or should be) legally possible for pharmaceutical
manufacturers to inform prescribers and other individuals
and groups about the likely costs and benefits of
unlicensed medicines uses, as and when off-label use is
known to be taking place or new evidence of significant
positive or negative impacts is available. This last to a
degree touches on issues such as the desirability and
viability of conditional or adaptive medicines licensing
in areas such as, say, cancer care (Eichler et al, 2012;
Eichler et al, 2009). Key questions here relate to the
extent to which future approaches to granting marketing
authorisations will allow for the regulated evolution
of clinical practice in ways which are practicable and
desirable from the perspectives of all the stakeholders
involved in health and health care improvement.
Once again, it is not possible here to explore such issues
in depth. But two main points are worth stressing. The
first is that events ranging from the recent experiences of
the General Medical Council (GMC) in relation to issuing
prescribing guidance through to that of (what were at the
time) Dorset PCTs seeking to prevent the use of a costly
but licensed presentation of amifampridine phosphate
(Firdapse) demonstrate that seeking to promote
unauthorised medicines prescribing on grounds other
than enhancing individual patient wellbeing is at best
problematic. Indeed, the EU Court of Justice’s recent
ruling on Polish government attempts to promote
unlicensed drug use (see Box 5) indicate that it should
be regarded as unlawful throughout Europe. ‘The core
principle of EU pharmaceutical legislation is that the
interests of public health and the medical needs of the
patient take precedence [over cost cutting]’ (Bogaert
and Schabl, 2012).
Following on from this, a second point to emphasise
is that medical practitioners would be in a potentially
vulnerable legal position if they were, regardless of any
third party advice given to them, to recommend an
unlicensed treatment primarily to save money and an
untoward event were to occur. Throughout the OECD
and increasingly the emergent economies the direction of
regulatory policy is to promote authorised – appropriately
licensed – medicines use whenever possible.
This does not, of course, mean to say that responsible
clinicians should shy from actions that they genuinely
believe could enhance health outcomes for their patients.
Nor ought it be taken as a denial of the fact that the
transition to a situation in which appropriately licensed
medicines are used whenever possible may on occasions
impose financial costs that, when considered in isolation
from wider policy concerns, seem hard if not impossible
to justify. (See, for instance, Ferner and Hughes, 2010;
Godlee, 2010.) But it does call into question conducting
cost effectiveness appraisals in ways that, intentionally or
not, can cause practitioners to think that using cheaper
unlicensed drugs when fully authorised alternatives exist
is an inherently ethical choice. It also underlines the fact
Box 5 Poland’s pursuit of low cost unlicensed pharmaceutical supplies
In the UK the General Medical Council (which
regulates doctors’ conduct) recently prepared revised
guidance that would have encouraged doctors to
prescribe medicines for unlicensed indications for
cost saving purposes. The motivations underpinning
this initiative included both perceived ethical and
political positioning elements (Davies, 2013). Yet
following challenges from both industry and regulatory
sources, the advice received by the GMC about the
desirability of this approach eventually led to a reversal
of the proposed changes. Likewise, PCTs seeking
to save money by forbidding the prescribing of
Firdapse, a costly but uniquely licensed presentation
of amifampridine for the treatment of a condition
called Lambert-Eaton Myasthenic Syndrome (LEMS),
withdrew their instructions to doctors when its legality
was questioned.
At the European level, Directive 2001/83/EC on the
Community code relating to medicinal products for
human use says that no medicine should be on the
market of a Member State unless it has a European
Commission marketing authorisation or one issued
by the State concerned. But there are special needs
criteria which allow unlicensed drugs to be supplied
when needed to meet individuals’ particular medical
requirements.
Calling on the principle of exception, Polish
legislation introduced in 2007 sought to permit
low cost pharmaceuticals with the same specified
make-up as products already available locally to
be imported from abroad, even though they were
lacking either EU or local marketing authorisations
(Killick and Kritikos, 2012). Although Poland is a
low overall spender on pharmaceuticals and health
care more broadly, poor access to treatments and
relatively high consumer costs have been a cause of
political concern. This action was intended to help
reduce such problems.
However, the European Court of Justice subsequently
found that Poland had failed to fulfil its obligations
under European Law (Court of Justice of the European
Union, 2012). Seeking to save money on medicines
(or any other type of product or service, including
doctors’ and lawyers’ fees) is an entirely reasonable
goal. But there are also public interests in maintaining
safety and quality through rigorous approaches to
licensing, just as there are in incentivising innovation
through granting IPRs. This judgement against Poland
not only confirms the fact that it is inconsistent with
European law to promote unlicensed medicine uses
for purely cost saving purposes, but also illustrates
the fact that no form of expenditure reduction is
desirable at any price.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
9
that in the 21st century there should not be one law for
the research based pharmaceutical industry and another,
laxer and less coherently enforced, one elsewhere in
health care.
Compassionate drug supply
The ‘compassionate’ provision of medicines differs from
‘off-label’ use as defined here in that products employed
for this purpose are typically in active development
and are so not as yet licensed for any indication. In the
1990s in the US the FDA introduced a ‘compassionate
use policy’. This meant that unlicensed drugs could be
employed to treat life-threatening diseases when no
alternatives existed and when trials of the former were
under way, or the manufacturer had formally applied for
FDA approval (Jacobson and Parmet, 2007).
Following this, the Abigail Alliance for Better Access to
Developmental Drugs was founded in 2001 by Frank
Burroughs, the father of a nineteen year named Abigail
Burroughs. She had died of a form of neck cancer earlier
in that year. Acting on the advice of a Johns Hopkins
Hospital based oncologist, her family had tried to obtain
an (at that time) unlicensed drug in an attempt to save
her life. But they were unable to do so.
In understanding this situation it should be born in mind
that at present advanced anti-cancer medicines may
extend lives, yet are rarely curative. In addition, they can
themselves have unpleasant and life threatening side
effects. However, it is entirely understandable that some
individuals may, when facing the prospect of an untimely
death for themselves or a loved one, wish to risk taking
experimental treatments. Some might do so in order to
make their lives and deaths more meaningful, by adding
to the stock of therapeutic knowledge available for the
future.
In the UK the proponents of the Medical Innovation Bill
(including Lord Maurice Saatchi, whose wife Josephine
Hart died from ovarian cancer in 2011) have pursued aims
similar to those of the Abigail Alliance. Yet recent legal
action has established that in the US today no patient has
an unqualified right to access unlicensed medicines for
which there is no evidence of therapeutic effectiveness.
An empathetic concern for everyone facing life limiting or
life changing illness is clearly desirable, and there is good
reason to be as flexible as possible in designing research
approaches in areas such as cancer care. But several of
the respondents who took part in the qualitative research
summarised in this report stressed that the overall public
has interests in maintaining a disciplined approach to
developing new drugs that guards against what could
at worse represent ‘a return to anarchic quackery’. (See
also Pollack, 2007; Caplan, 2007.)
A recent article in the New York Times by a paediatric
cardiologist summed up from a North American
perspective the problems inherent in both ‘compassionate
use’ and the prescribing of licensed medicines for
unlicensed indications. The author and his medically
qualified sister had campaigned for their father, who was
dying from a condition involving pulmonary fibrosis (lung
10
scaring), to have access to an unlicensed medicine. They
succeeded, but in the event the drug not only failed to
alleviate his distress but sadly caused fevers and severe
pain. On the other hand, the author also described his
experience of helping a young mother extend her life
by what were to her and her family four valuable years
through the use of an unlicensed treatment (Sanghavi,
2013).
In the European context Regulation 726/2004/EC allows
for the supply of experimental medicinal therapies in
some circumstances. It permits ‘groups of patients with a
chronic, seriously debilitating or life-threatening disease,
without a satisfactory authorised treatment available,
and who cannot take part in a clinical trial, access to
an unlicensed medical product’ (Whitfield et al., 2010).
Yet there is evidence of considerable variation in the
interpretation of this provision. A number of EU countries
have no formal system in place to facilitate and manage
‘compassionate’ prescribing and supply. In practice,
responsibility rests solely with the doctor concerned.
It is also of note that in the UK patients involved in clinical
trials can continue to use the drug(s) concerned after
the trial is over and before a license has been awarded
under the ‘expanded access’ policy, and that the MHRA
has issued a guideline on providing unlicensed medicinal
products for individual patients (MHRA, 2013). There is
no doubt that unlicensed drug use sometimes improves
outcomes, although observers such as Whitfield and
her colleagues are critical of the term compassionate
prescribing. They argue that acting with compassion
is ‘a fundamental principle throughout healthcare’
and that allowing access to ‘medicinal products with
little knowledge of their benefit or harm should not be
labelled as the most compassionate strategy’. These
authors (Whitfield et al., 2010) refer instead to ‘expanded
access’. The latter concept is beginning to be more
widely used to refer to the structured development of
flexible regulatory approaches to cases such as that of
Abigail Burroughs (FDA, 2010).
The utility of ICERs
A final issue to consider before turning directly to
NICE’s record in requesting the use of relatively low
cost unlicensed comparators in cost effectiveness
appraisals relates to the role of incremental cost effective
ratios (ICERs). The development of health economics
methodologies since the 1960s, led most notably
by economists working in the University of York, has
underpinned the creation of institutions such as the
National Institute for Health and Care Excellence in
England, as well as bodies like the Scottish Medicines
Consortium (SMC) and IQWiG in Germany.
Such thinking appears to have also influenced US
organisations such as the Federal Agency for Healthcare
Research and Quality (AHRQ), albeit that the PatientCentered Outcomes Research Institute (PCORI) recently
established via President Obama’s Patient Protection
and Affordable Care Act is specifically precluded from
using an ICER based approach. US political decision
makers appear to fear (despite America’s chequered
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
record with regard to health inequalities) its potentially
negative impacts on the provision of health and welfare
services and in particular the Constitutional ideal of
respecting all individuals’ rights equally, regardless of
factors such as their age and health status.
A key step forward in the evolution of health technology
assessments was, from the 1980s onwards, the
introduction of the Quality Adjusted Life Year (QALY).
Although in practice quality of life is very difficult to assess
with accuracy and sensitivity, ‘cost per QALY’ estimates
can compare the relative utility of interventions between
differing fields. They hence permit ‘value for money’
comparisons across the health arena as a whole.
A QALY is the sum of any life extension period that a
treatment may offer and its impact on the projected
quality of life for the individual receiving the intervention.
As such, QALYs involve a pragmatic combination of
factors which as a single measure of worth/value can be
useful but may be flawed in its implications. For instance,
although two people may agree that the quality of their
lives is different, they may not accept that the overall
amount of money available to save either of their lives
at any given point should differ because one is younger
and healthier than the other. Others, by contrast, may
wish to value ‘different’ QALY’s at markedly varying levels
of affordability, depending on their social and clinical
contexts.
ICERs contribute to health economic evaluations by in
essence highlighting the extra cost per additional QALY
gained from delivering a new treatment as opposed to the
best established alternative (the comparator) available
at any one point in time. But an important observation
to make is that although a new treatment may, for a
proportion of individuals, be significantly better than any
other available, and its absolute cost no more than other
medicines readily supplied by the health service, ICER
based calculations could make it seem unaffordable. The
factors that can contribute to this include the uncritical
use of aggregated data sets and the employment of
what some critics see as unrealistically low (commodity)
cost comparators in a proportion of cost effectiveness
calculations.6
In such circumstances an innovation may cost
an affordable amount – say £10,000 per person
successfully treated – but have an ICER based ‘cost per
marginal QALY’ of, say, £50,000 or more. At a political
and managerial level the significance of this distinction
does not seem to be widely understood, despite its
6 One possible line of argument is that – if providing incentives to
innovate is accepted as a key priority – licensed and IP protected
treatments should only be compared with similar products in any
given market environment. In Japan, for instance, it is not normal
practice to compare new medicines with generic presentations.
It might also be suggested that when suitable comparators are
not available then the average cost per QALY generated by
a treatment could be a more useful indicator of its value and
affordability than its ICER value calculated against the baseline
of a commodity cost comparator. However, this contradicts
deeply held beliefs underlying York school ‘value based pricing’
theory. A perhaps more acceptable alternative might be to use
model comparators, based on overall or selected sub-market
experience.
potential impacts on patient and public interests in long
term innovation. Further, were the cost of a comparator
treatment to fall (as happens when a product loses
intellectual property protection) a medicine could move
from being cost effective to non-cost effective, despite
its actual price and value to patients remaining constant.
Uncertainties linked to the possibility of such shifts
may block privately funded incremental (step by step)
innovation, even when the eventual returns for society
from continuing a development process might be many
orders of magnitude greater than the total research and
drug supply costs involved.
Such concerns suggest that – in circumstances where it
is agreed that continuing therapeutic improvements are
required because current generic (or newer) medicines
are only partially satisfactory – the use of ICER based
cost per QALY data to judge when treatments are above
or below a set affordability threshold can carry with it
considerable (albeit difficult to quantify) unanticipated
costs. This raises questions about, for instance, the
acceptability or otherwise of regarding people aged over
70 or 80 years as having had ‘a fair innings’(Williams,
1997) and hence no longer being eligible for life extending
and/or improving treatments afforded to younger and
healthier people
With regard to medicines pricing it may also be argued
that the most important purpose of the activities
undertaken by modern economic regulators in the
pharmaceutical sector is not to ‘fairly’ reward past
research expenditures, but rather to appropriately
incentivise future investment in innovation. If this is so,
then ICER based cost effectiveness data may have much
less value than is often assumed. In partially planned,
managed, markets dominated by public or neo-public
sector monopsonists (that is, large single purchasers)
the most important ‘price signals’ to give could well
relate more to equitable risk sharing than to underwriting
exceptional good fortune. If this view is accepted it has a
number of important implications. It could, for instance,
be regarded as a reason for permitting affordability
thresholds for rare indication treatments that are many
times greater than those for common conditions
therapies, independent of ‘Rawlsian’ calls for justice for
minority groups (see Rawlins, 2012).
For the purposes of this analysis, however, the
fundamental point to stress is that it is critically
important for agencies responsible for conducting cost
effectiveness analyses to select comparator medicines
carefully and with sensitive insight into overall public
policy ends. If cost minimisation is the highest priority
goal, then choosing the cheapest comparator, licensed
or otherwise, might be judged appropriate. But if
sustainable, long term, welfare improvement is desired,
then selecting more expensive ‘best existing licensed
treatment’ comparators may well be the best choice.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
11
NICE policies and practices: is
there evidence of direct or indirect
endorsement of unlicensed
medicines use for cost saving
purposes?
NICE was first established in 1999, following the
publication of a White Paper entitled ‘The New NHS:
modern, dependable’ by the then ‘new Labour’
government led by Tony Blair. As touched on above, its
creation took place after some 40 years of cumulative
health economics research funded both by public grants
and private companies. The latter were in part seeking to
encourage the NHS to accept cost saving and/or welfare
enhancing therapeutic innovations which would require
structural adjustments to release their full benefits.
Because NICE was able to build on this intellectual
heritage it has proved in many respects one of the most
– if not the most – successful of all the health service
reforms made since the initial major re-organisation of
1974.
The Secretary of State responsible for producing The
New NHS , Frank Dobson, placed strong emphasis on
the role he wanted NICE to play in reducing inequities
associated with so-called ‘post-code prescribing’ (BBC,
1999). But in addition to contributing to the reduction of
geographical variations in access to treatments resulting
from uncoordinated local rationing decisions, NICE
has since the start of the present century also made
important, and in the main high quality, inputs to medical
practice and public health improvement through the
development of evidence based guidelines.
In the area of health technology assessment NICE
has provided insights into the cost effectiveness of
existing and new treatments as evaluated on a cost
per QALY basis. Whereas before its establishment
medicines were, once licensed, introduced into NHS
use via an amalgam of national interventions, supply
side promotional activities and disseminated demand
side decision making, they should now be universally
available in England and Wales within months of when
NICE has pronounced them cost effective for use for
given licensed indications. (The organisations’ leaders
have repeatedly explained that, as for example with the
early stage use of the breast cancer treatment Herceptin,
it is not in a position to recommend unlicensed uses of
innovative treatments, even when there is good reason
to believe that they would enhance welfare in ways not
previously possible – Rawlins et al, 2010).
At the strategic policy level, NICE has to a degree
served as an instrument for extending the regulation
of medicines supply via imposing indirect limits on
individual product prices and/or NHS treatment access.
In parallel with this, it also acts as a mechanism for
shaping the ways in which doctors and institutions
care for patients. NICE’s established remit includes
comparing the ‘value for money’ offered by new
products against the comparators that ‘may not have
a marketing authorisation for the indication defined in
12
the scope but that are used routinely for the indication
in the NHS.’ (NICE, 2013). As such, the organisation
is in a position to actively influence present and future
attitudes and behaviours as to the extent to which
unlicensed medicines are used in the health service
for cost saving purposes, alongside its overt role in
supporting the use of innovative products for their duly
licensed indications.
In order to understand this field further, Kusel and her
colleagues in the Cambridge based company Costello
Medical Consulting published in 2013 the results of
an analysis of 91 Single Technology Appraisals (STAs)
conducted between 2008 and the end of 2012. Their
goals included measuring the frequency with which
the NICE has requested companies that have sought
to establish the cost-effectiveness of their products
to provide data on off-label comparator applications,
and assessing the consequences of complying with
or refusing such requests. With support from the UCL
School of Pharmacy, this work was updated at the
end of 2013 to include all the scopes (initial information
requests) for STAs published between 1st January 2008
and 18th December 20137 (Kusel et al, 2013).
In all there were 31 instances in which at least one offlabel comparator was requested out of a total of 111
STAs undertaken. This represented 28 per cent of the
global number of Single Technology Appraisals found –
see Figure 2. Initially, NICE in 8 of those 31 instances
(that is, about a quarter of the cases where a nonlicensed comparator was suggested, or 7 per cent of
all STAs) appeared to have rejected the new product in
favour of the unlicensed drug, or because the requested
‘off-label’ comparison data was not supplied by the
innovator. However, in 2 of these cases the rejection
decision has since been changed. Figures 3, 4 and 5
show that the proportion of scopes with an unlicensed
comparator request was higher in 2013 than it was in
any previous year.
However, when seen in the round NICE has only rejected
new technologies in favour of unlicensed alternatives in
a comparatively few instances. It has on more occasions
recommended NHS use even manufacturers have
decided not to comply with requests for ‘off-label’/
unlicensed comparator data. With regard to the latter,
the Costello analysis indicates that since it was ruled in
September 2012 that the makers of belimubab (Benlysta)
were not responsible for producing information on using
the monoclonal antibody rituximab (MabThera) for
the treatment of the occasionally fatal (and frequently
7 In cases where STAs had been updated only the most
recent versions were included in the data offered here. Offlabel comparators were identified as being used outside the
licensed indications as reported by the EMA and/or in the
Electronic Medicines Compendium. In cases where off-label
comparators were requested by NICE in the initial STA scope,
the Manufacturers’ Submission (MS), the Evidence Review
Group report (ERGs are independent groups charge by NICE
with evaluating MSs – see Kaltenthaler et al 2012) and the Final
Guidance Determinations (FADs) were reviewed in order to
ascertain the impacts of compliance and non-compliance on
application outcomes.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
Figure 2: Proportion of all TAs where an
off-label comparator was requested by NICE
2008-2013
Figure 3: Number of off-label
comparators requested in the period
2008-2013
Source: Kusel et al, 2013
Source: Kusel et al, 2013
Figure 4: Outcome of cases where the
manufacturer performed the requested
unlicensed comparator drug evaluation
Figure 5: Outcome of cases where the
manufacturer did not perform the comparison
requested
Source: Kusel et al, 2013
Source: Kusel et al, 2013
disabling) auto-immune disease Serum Lupus
Erythematosus (SLE), there has been less willingness
on the part of manufacturers to comply with what may
be seen as potentially costly and inappropriate NICE
requests for data relating to unlicensed comparators
(Kusel,2013).
equity perspective it is also hard to comprehend why
the innovative company responsible for developing
belimumab should have been expected to fund further
research on the effectiveness of rituximab for the
treatment of an unlicensed indication, and appropriate
that NICE’s request was eventually judged incorrect.
In this particular instance, SLE is most prevalent in
women of non-European descent. White men are
relatively rarely affected. Rituximab was first introduced
in the US in the late 1990s, initially for the treatment of
a form of lymphoma. It has subsequently been licensed
for modifying the course of rheumatoid arthritis. Its
authorised use in Europe is somewhat more restricted
than it is in the United States, but (notwithstanding
some clinical studies) in neither America nor the EU has
rituximab been licensed for the treatment of people who
have developed SLE.
The motivation underlying the initial NICE request
therefore appears difficult to understand from a patient
interest perspective. Like rituximab, belimumab acts
on B lymphocytes. Yet it does so via a distinct mode
of action that is less toxic to such cells and has been
specifically researched in the SLE context. From an
Public interests in safe and sustainable
innovation
In overview, NICE has to date frequently requested
comparisons with non-licensed medicines. In some
cases new interventions have been rejected in favour
of unlicensed comparators, although it should not be
assumed that this was only because of a desire for
cost savings. The available data indicates that NICE
has normally been prepared to accept manufacturers’
decisions not to provide data on unlicensed comparators.
Yet delays in providing treatment to NHS patients
have been caused, and when data on the relative
efficacy of unlicensed comparators has been provided
it has sometimes been used as evidence of non-cost
effectiveness.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
13
Box 6 Supporting unlicensed drug use?
Part of the background to recent debate surrounding
issues such as NICE’s apparent support for the
unlicensed prescription of risperidone for health service
users aged under 18 is that US law was changed in
the late 1990s to permit companies to inform doctors
about potential ‘off-label’ product uses by, for instance,
supplying articles discussing such applications. The
American legislation was, however, changed back
again about a decade later. Events such as research
based pharmaceutical companies being fined for
inappropriate promotion should be understood in the
light of this process, and the complex legal and public
interest debates that attended it.
One-sided views that misleadingly stereotype
pharmaceutical companies as being motivated by antisocial objectives or regulators as being insensitive to
individual needs on the one hand or blind to the wider
social benefits of pharmaceutical innovation on the
other should be avoided. The position taken here is that
licensed medicines use should be facilitated whenever
possible, but that that there will be exceptions to this
rule. Neither pharmaceutical company nor health care
funder and provider based critics of a rigid adherence
to it should be automatically dismissed as lacking
ethical motivation.
The treatment with psychotropic medicines of children
and ‘adolescents’ who have mental health problems is
often controversial. Accepted US psychiatric practice
differs markedly from European approaches, and it is
always the case that ‘pills are not skills’. Interventions
made with pharmacologically active agents may, for
example, have beneficial (direct and/or epigenetically
As Box 6 describes, there have also been occasions
when NICE guidelines appear implicitly or explicitly to be
promoting the use of low cost alternatives to licensed
therapies, even though the latter have been accepted as
sufficiently cost effective for NHS use. A recent example
of this has been the suggestion that patients aged under
18 who have been diagnosed with schizophrenia should
in the first instance be offered risperidone – which is now
available as a low cost generic medicine – rather than
aripiprizole (Abilify) (NICE 2011a).
Aripiprizole is licensed for use in patients aged under 18
while risperidone is not. The licensed product may as
discussed in Box 6 have some limited clinical advantages
relevant to younger people. But at present it costs
more than risperidone because it still enjoys intellectual
property protection. In the past, when risperidone was
still under patent and only available under the brand
name Risperdal, its producers were fined in the US for
promoting it for unlicensed – if not necessarily clinically
inappropriate – uses.
Attitudes towards such issues are variable. One
individual with a robust understanding of national policy
and NICE’s remit and practices indicated that in his view
it is not a matter of concern to the Institute whether
14
mediated) impacts in instances where individuals have
been exposed to unusually stressful experiences. Yet
they can never substitute for enabling people to gain
the social and psychological competencies they need
to cope with their lives.
In the case of aripiprizole ‘versus’ risperidone it is
certainly the case that both drugs have similar effects
on brain chemistry, and that promoting the wellbeing
and protecting the interests of young people suffering
schizophreniform illnesses (or indeed states such as
depression) depends on more than the ‘correct’ drug
selection. Even so, it is important that aripiprizole is
licensed for use in people aged under 18. It may also be
relevant to record that the available literature indicates
that aripiprizole may be less likely to be associated with
unwanted weight gain than some other anti-psychotics
(Murray, 2014). Weight gains amongst people living
with schizophrenia can lead on to later life problems
such as type 2 diabetes.
Another relatively recent example of NICE guiding
prescribers towards unlicensed medicines use despite
an apparent awareness of current European law can be
taken from the updated guidance on the treatment of
generalised anxiety disorder (GAD – NICE, 2011b). This
at one point recommends: ‘Consider offering sertraline
first because it is the most cost-effective drug, but note
that at the time of publication (January 2011) sertraline
did not have UK marketing authorisation.’ Once again,
it would be misleading to suggest that such advice is
likely to have significant impacts on patient safety or
health outcomes at the personal level. But from an
overall policy perspective it is highly questionable.
or not a medicine is licensed for an indication (‘that is
not [NICE’s] problem’). The implicit attitude underlying
responses of this type appears to be that NICE can
and should unilaterally judge whether or not there is
satisfactory evidence of unlicensed medicine uses being
safe, effective and cost saving. This respondent also
believed that health service users should do more to
question the high prices of new medicines, regardless
of the impacts of the Pharmaceutical Price Regulation
Scheme and national and global public interests in
maintaining the viability of private and public investment
in biopharmaceutical research.
A senior NHS pharmacist with extensive hospital
experience offered a very similar view. This individual
indicated an implicit belief that a competent pharmacist
would be failing in his or her duty to their organisation if
a cheaper medicine that could in all known probability
be used safely was not substituted for a more costly
presentation, regardless of its formal licensing.
By contrast, a NICE staff member acknowledged the
existence of ethical and legal problems in relation to
directly or indirectly recommending unlicensed drug
use when licensed products are available. So too did
some other senior NHS pharmacists and medicines
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
regulators. Yet some other individuals approached
were very reluctant to discuss this area. There appear
in certain settings to be fears, valid or otherwise, of
disciplinary interventions and/or institutional damage
that are influencing the willingness of public servants and
individuals with regulatory responsibilities to contribute
to public debate on this topic.
One professional respondent suggested that such
restraints are stronger in Britain than in some other
European countries. At the same time others noted
that the employees of privately owned research based
companies, and also people working in organisations
providing them with services or receiving grants, may
on occasion also feel unable to express honestly their
personal views in public.
Amongst patient representatives interviewed there was
a general acceptance of the desirability of using licensed
medicines whenever available, alongside a belief that
‘the health service needs to make money go as far as
possible’. Similarly, respondents in this group recognised
the desirability of high risk research investments, but
also thought that pharmaceutical companies should
be prepared to lower their prices and profits in order to
benefit patients.
Over and above such apparent conflicts, a number of
the topics that this brief UCL School of Pharmacy report
touches on were outside the interests and experiences
of many of the (well informed) individuals who agreed to
contribute to the research undertaken. But with regard
to issues such as the paediatric medicines reforms
introduced in Europe to encourage clinical trials in
child populations together with appropriate medicines
licensing and use, there were again commonly
expressed ambiguities. All respondents supported the
principle of ensuring effective dosing and supplying
paediatric medicines in well-designed formulations. Yet
a proportion questioned whether or not the same drug
should cost more in one context than another.
As in the ‘ranibizumab versus bevacizumab’ debate
on the treatment of conditions like age related ‘wet’
macular degeneration, some individuals appear to be
unable or unwilling to differentiate between the value
of a medicine as represented by its impacts on clinical
outcomes and the levels of financial risk incurred during
its development, as opposed to the manufacturing cost
of the substances it contains. Likewise, neither patient
representatives nor NHS interviewees articulated without
prompting an awareness of the fact that although health
care interventions demanding human labour are always
likely to cost about the same amount, the supply cost of
innovative medicines normally falls dramatically within 1015 years of their initial marketing because of IPR expiries.
On the basis of the qualitative interview findings conducted
for this study, industry linked observers (including people
based in academia) are by contrast much more aware
of the significance of such factors. One individual with
unique experience of developing a children’s medicine
containing a mature active pharmaceutical ingredient
previously only licensed for adult use commented ‘the
real problem is not that [repurposed and other] medicines
are too expensive, its that the incentives to develop
them are still too weak. With regulatory data exclusivity
all a competitor has to do is copy your work so unless
there is a special step why bother?’. The importance
of this observation is highlighted by evidence that
when medicines such as midazolam (now available as
Buccolam) are reformulated and licensed for specialised
paediatric use there can be significant advantages for
the children being treated (Tomlin, 2011).
In general, industry based interviewees saw NICE’s
requests for unlicensed comparator information as unfair
and a future threat to the viability of the research based
pharmaceutical industry and the patient and public
benefits it generates. In contexts such as that of cancer
treatment some questioned this and the wider approach
adopted in England and Wales as compared to that
believed to be favoured by the SMC (Box 7).
One interviewee said ‘it may not be that much of a
problem now, but it could be soon. The use of generics
as comparators is already blocking progress in a lot of
areas and this [the use of unlicensed comparators in
cost effectiveness appraisals] could make things a lot
worse. They are stealing the meaning of value.’ Another
commented ‘the Scottish Medicines Consortium seems
to have a more reasonable approach, without pushing
unlicensed medicines uses. We need to be clear about
whether NICE is supposed to be taking into account the
importance of licensed use when companies have to play
by the rules. What will happen if we lose more [research
based industry]?’ However, other sources denied that
SMC has a consistent policy against the use of unlicensed
comparators in cost effectiveness assessments.
Conclusions and recommendations
The National Institute for Health and Care Excellence has
many positive achievements to its credit, and exercises
a growing world-wide influence on the ways medicines
and other treatments are valued and used. It is therefore
important that the approaches it adopts are as far as
is possible in line with national and international public
interests. The pursuit of narrowly defined health care
provider ‘value’ may or may not be consistent with the
legislation that today underpins the existence of the
National Institute as an ‘executive non-departmental
body.’8 But it clearly does not encompass the full range
of benefits many patients and members of the public
consider relevant to comprehensively determining the
worth of modern medicines and ongoing biomedical
research.
8 Until April 2013 NICE was a Special Health Authority within
the NHS. Some commentators argue that if NICE is not now
mandated to take fully into account the extra-NHS/health sector
benefits of therapeutic innovation, this can and should be
remedied by other government departments. Special Treasury
support for research investors and patent holders may be taken
as an example. However, in a global market the use of what could
be regarded as distorting subsidies in atypical settings like the UK
might in overall terms impact very negatively on research funding
and the improvement of public health, and hence on wider British
public interests.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
15
Box 7 The Scottish Medicines Consortium (SMC) and public concerns about cancer care
The SMC was first established in 2001, approaching
two years after NICE. Its remit is ‘to provide advice to
NHS Boards and their Area Drug and Therapeutics
Committees (ADTCs) across Scotland about the status
of all newly licensed medicines, all new formulations of
existing medicines and new indications for products
licensed from January 2002.’ Quality Improvement
Scotland (QIS) reviews all NICE Multiple Technology
Assessments (MTAs) and decides whether or not they
should apply in Scotland. If so, the NICE guidance
supersedes SMC advice. However, NICE Single
Technology Appraisals (STAs) have no status in Scotland
Some observers regard the SMC’s approach as being
superior to that of NICE in areas like assessing the
value of new anti-cancer treatments. One clinician with
relevant experience commented ‘I think their [the SMC’s]
technical advice is better’. Others privately suggest
that English advisory committees can be dominated by
agency staff members with fixed attitudes towards how
‘health economics’ based assessments should properly
be conducted, and who may rule information thought
important by clinical and other experts to be irrelevant.
Such evidence is essentially anecdotal. But it is of
note that in the context of cancer treatment there is
no equivalent to the Cancer Drug Fund that covers
England. This is also true in Wales, which is subject to
NICE judgments but has no CDF equivalent. Access to
The record to date of NICE in requiring ‘off-label’ (and
so in indication specific terms unlicensed) medicines
to be employed as comparators in cost effectiveness
studies, and in subsequently recommending that low
cost unlicensed products be used in preference to
licensed alternatives, cannot to date reasonably be
said to have significantly undermined public health.
But without a commitment to unequivocally supporting
licensed medicinal product use whenever this is
consistent with patients’ best clinically defined needs,
and to calculating cost effectiveness in ways which
optimally reflect public interests in both safety and the
ongoing development of better therapies, NICE HTAs
might nevertheless in future cause more overall harm
rather than benefit.
A more precise definition of what is considered
‘established health service practice’ than that currently
in the literature about the National Institute Health
and Care Excellence’s remit might help to minimise
such risks. Failures to develop an intellectually robust
framework for judging when – if ever – it is correct for
unlicensed uses of IP protected or generic treatments
to be accepted as ‘established’ rather than undesirable
could lead agencies such as NICE to undermine the
work of bodies such as the MHRA and the EMA. At
worst, the Institute will become a serial instigator of
new unlicensed medical interventions. This might on
occasions permit the pursuit of financial savings to
16
anti-cancer medicines there may as a result be more
restricted than in other parts of Britain. In England, the
CDF currently spends in the order of £250 million per
annum funding anti-cancer treatments that NICE has
not judged cost effective. The total cost of all (NICE and
CDF ‘approved’ plus other) pharmaceutical products for
patients with cancer in England is in the order of £1.2
billion per annum, which is about 1 per cent of all NHS
spending and 0.1 per cent of GDP. These last figures
have stayed broadly constant for well over a decade.
The existence of the CDF has helped to reduce, but not
eliminate, English public fears that NHS patient access
to anti-cancer treatments is inadequate, and so to limit
associated political problems. But in the context of this
paper it also raises implicit public and political concerns
about the ways cancer treatments are evaluated by NICE,
and the underlying integrity and social acceptability of its
methodologies in areas such as comparator selection
in cost effectiveness appraisals. From a public health
perspective, the most effective ways forward in reducing
cancer related harm must of course focus on primary
prevention and ensuring optimal early stage detection
and cure rates. Yet it is also a demonstrable social fact
the British public highly values research into treatments
for established cancers. The existence of the Cancer
Drug Fund raises questions as to whether or not this
reality has been fully respected by NICE.
distort awareness of patients’ and the wider public’s
best interests.
Seen from this last perspective, it may be concluded
that in future NICE should avoid proposing the use
of unlicensed medicines as comparators to licensed
products in cost effectiveness appraisals.9 However, it
is also realistic to conclude that there will be continuing
political and managerial demands for NICE and similar
bodies to provide estimates of the value of medicines
on a product by product basis, despite the fact that
interventions such as ‘drug budget capping’ suggest
that the utility of such data is less than commonly
believed. If this is the case then NICE and its external
stakeholders may wish to consider anew the extent to
which its current approach to determining ‘incremental
QALY’ based cost effectiveness ratios, combined with
relatively inflexible affordability criteria, are a logically or
ethically acceptable guide to the evaluation and pricing
of innovative therapies.
The need for open and informed public debate is at
its greatest in circumstances where it is not genuinely
possible to identify suitably licensed comparators. It is
also pressing in contexts where the further improvement
of existing therapies is a recognised social priority, even
9 If products have not been rigorously trialled they may, ‘established
uses’ or not, be a source of inadequately quantified harm. This
was arguably illustrated by the recent withdrawal of the weightloss drug benfluorex (Mediator) in France.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
though substantive progress may demand decades
of sustained high risk private and public investment.
Investigating disease states or scientifically important
biological phenomena underlying them is likely to be
especially difficult in contexts where even when they
have been understood they require only relatively
infrequent clinical interventions, and so offer only limited
overall commercial and national income generation
opportunities.
There are significant technical and political hurdles
to be overcome in addressing the various challenges
touched on in this report. Yet changes such as those
presently involving the UK PPRS suggest that it should
be possible to find ways of simplifying and reducing
the costs of current treatment affordability calculations.
Such progress might also help reduce needless patient
fears that they will not be able to obtain ‘cutting-edge’
treatments, without abandoning the useful work of HTA
agencies in areas like evidence based clinical guideline
development and multiple technology assessments.
Further progress in fields such as characterising ‘model’
or proxy comparators for use in cost effectiveness
assessments might help to resolve controversies
about assuring timely access to anti-cancer medicines,
providing new treatments for rare disorders, and
equitably pursuing ‘healthy ageing’.
In the final analysis, the purpose of conducting health
technology assessments is to enable individuals to
access treatments they want and can benefit from, and
at the same time to help societies move towards the
futures the people in them collectively judge desirable
in an efficient and affordable manner. Superficially,
questions relating to the unlicensed use of low cost
medicines as comparators in cost effectiveness
appraisals of licensed pharmaceutical products may
seem to have little bearing on the achievement of such
fundamentally important human goals. Yet the reality is
that inappropriate approaches to valuing new treatments
and health care more broadly could distort decision
making and undermine national and global welfare. Such
errors must be avoided if the combined promise of the
biopharmaceutical and modern economic and other
social sciences is to be fully realised as the twenty first
century unfolds.
References and Further Reading
Abraham J & Davis C (2006) Testing times: the emergence of
the practolol disaster and its challenge to British drug
regulation in the modern period. Social History of Medicine
19, 127-47.
Anon (1992) Prescribing unlicensed drugs or using drugs for
unlicensed indications. Drug and Therapeutics Bulletin 30,
97-9.
Anon (2008) Whale slams ‘barbaric’ drugs ruling. URL http://
www.express.co.uk/news/showbiz/55786/Whale-slamsbarbaric-drugs-ruling#.
Anon (2010) A battle over orphan drug pricing in the UK. URL
http://www.pharmalive.com/battle-over-orphan-drug-pricinguk.
Ashburn T T & Thor K B (2004) Drug repositioning: identifying
and developing new uses for existing drugs. Nature reviews
Drug discovery 3, 673-83.
Avorn J (2011) Learning about the safety of drugs—a
half-century of evolution. New England Journal of Medicine
365, 2151-3.
Baldwin D S & Kosky N (2007) Off-label prescribing in
psychiatric practice. Advances in psychiatric treatment 13,
414-22.
Barker R (2010) A flexible blueprint for the future of drug
development. The Lancet 375, 357-9.
Bartrip P (1992) A” pennurth of arsenic for rat poison”: the
Arsenic Act, 1851 and the prevention of secret poisoning.
Medical History 36, 53.
BBC (1999) Public health white paper in depth.
Beckford M (2011) Doctors could be allowed to prescribe
cheap medicine against drug companies’ wishes.. URL http://
www.telegraph.co.uk/health/healthnews/8433275/Doctorscould-be-allowed-to-prescribe-cheap-drugs.html.
Bogaert P & Schwabl A (2012) Cost considerations should
not drive off-label drug use in EU. URL http://www.cov.com/
files/Publication/8f75bfde-db06-4f50-914f-c641f2d4fa57/
Presentation/PublicationAttachment/a9c97b58-fec8-4f298101-ca7cef768d24/Cost_Considerations_Should_Not_
Drive_Off-label_Drug_Use_in_EU.pdf.
Boguski M S, et al. (2009) Repurposing with a difference.
Science 324, 1394.
Boseley S (2002) EU loophole sends drug prices soaring.
URL http://www.theguardian.com/society/2002/jun/24/
health.medicineandhealth1/print.
Braillon A (2011) Mediator: who’s to blame? The Lancet 377,
2003-4.
Briggs H (2013) MS hope from ‘off the shelf’ drugs. URL
http://www.bbc.co.uk/news/health-23327835.
Caplan A (2007) Is it sound public policy to let the terminally ill
access experimental medical innovations?
CBSNews (2013) Johnson and Johnson to pay $2.2B in U.S.
health care fraud settlement.. URL http://www.cbsnews.com/
news/johnson-johnson-to-pay-22b-in-us-health-care-fraudsettlement/.
Cheung C M G & Wong T Y (2013) Treatment of age-related
macular degeneration. The Lancet 382, 1230-2.
Cheung N, et al. (2012) Anti-vascular endothelial growth
factor treatment for eye diseases. BMJ: British Medical
Journal 344.
Chisholm A (2013) Prescribing outside of a drug’s licence:
issues and implications. Prescriber 24, 27-32.
Court of Justice of the European Union (2012) Polish
legislation authorising the placing on the market of foreign
medicinal products lackng authorisation which are cheaper
than, but similar to, those already authorised is contrary to
European Union law. URL http://curia.europa.eu/jcms/upload/
docs/application/pdf/2012-03/cp120036en.pdf.
Currow D C (2010) Why don’t we do more rigorous clinical
research so that we can stop experimenting on patients? J
Palliat Med 13, 636-7.
Davies M (2013) GMC does u-turn on extending use of
off-label medicine. URL http://www.pulsetoday.co.uk/
your-practice/practice-topics/regulation/gmc-does-u-turn-onextending-use-of-off-label-medicines/20001699.article#.
UrRxtfS3M1M.
Dawson W (2014) Personal Communication.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
17
Dent L & Raftery J (2011) Treatment success in pragmatic
randomised controlled trials: a review of trials funded by the
UK Health Technology Assessment programme. Trials 12,
109.
Djulbegovic B, et al. (2012) New treatments compared to
established treatments in randomized trials. Cochrane
Database Syst Rev 10.
Godlee F (2010) Stop exploiting orpham drugs. URL http://
www.bmj.com.libproxy.ucl.ac.uk/content/341/bmj.
c6587#alternate.
Goldacre B (2012) Bad Pharma: How drug companies
mislead doctors and harm patients. Fourth Estate, London.
Dresser R (2007) The curious case of off-label use. Hastings
Center Report 37, 9-11.
Greene T (2011) Detrol settlement of $14.5 million adds to list
of off-label cases under false claims act. URL http://
falseclaimsactattorney.com/2011/10/detrol-settlement-14-5million-adds-list-off-label-cases-false-claims-act/.
Dresser R & Frader J (2009) Off-Label Prescribing: A Call for
Heightened Professional and Government Oversight. The
Journal of Law, Medicine & Ethics 37, 476-86.
Gupta S C, et al. (2013) Cancer drug discovery by
repurposing: teaching new tricks to old dogs. Trends in
Pharmacological Sciences 34, 508-17.
Drummond M & Mason A (2009) Rationing new medicines in
the UK. BMJ 338.
Harris Interactive (2013) U.S. adults ambivalent about the
risks and benefits of off-label prescription drug use. URL
http://www.prnewswire.com/news-releases/us-adultsambivalent-about-the-risks-and-benefits-of-off-labelprescription-drug-use-56012072.html.
Drummond M & Sorenson C (2009) Can NICE be nicer? In a
world of budget constraints there are no easy solutions. Value
in Health 12, 634-6.
Dyer C (2011) GMC consults doctors on prescribing cheap
unlicensed drugs to save money. URL http://www.bmj.com/
content/342/bmj.d2263.
Haw C & Stubbs J (2005) A survey of the off-label use of
mood stabilizers in a large psychiatric hospital. Journal of
Psychopharmacology 19, 402-7.
Eichler H-G, et al. (2009) Safe drugs and the cost of good
intentions. New England Journal of Medicine 360, 1378-80.
Haw C & Stubbs J (2007a) Benzodiazepines—a necessary
evil? A survey of prescribing at a specialist UK psychiatric
hospital. Journal of Psychopharmacology 21, 645-9.
Eichler H-G, et al. (2010) Relative efficacy of drugs: an
emerging issue between regulatory agencies and third-party
payers. Nature reviews Drug discovery 9, 277-91.
Haw C & Stubbs J (2007b) Off-label use of antipsychotics: are
we mad?
Eichler H-G, et al. (2012) Adaptive licensing: taking the next
step in the evolution of drug approval. Clinical Pharmacology
and Therapeutics 91, 426-37.
Ekins-Daukes S, et al. (2005) Off-label prescribing to children:
attitudes and experience of general practitioners. British
Journal of Clinical Pharmacology 60, 145-9.
Emanuel M, et al. (2012) Thalidomide and its sequelae. The
Lancet 380, 781-3.
European Parliament Directive 2001/83/EC of the European
Parliament and of the Council of 6 November 2001 on the
Coomunity code relating to medicinal products for human
use. URL http://www.mhra.gov.uk/home/groups/es-herbal/
documents/websiteresources/con009360.pdf.
FDA (2010) Access to investigational dfrugs outside of a
clinical trial (expanded access).. URL http://www.fda.gov/
ForConsumers/ByAudience/ForPatientAdvocates/
AccesstoInvestigationalDrugs/ucm176098.htm.
Ferner R E & Hughes D A (2010) The problem of orphan
drugs. BMJ 341, c6456.
Feuerstein A (2013) Catalyst pharma: orphan drug poseur,
profiteer. URL http://www.thestreet.com/print/
story/12073358.html.
Hawkes N & Cohen D (2010) What makes an orphan drug?
BMJ 341.
Healy D & Nutt D (1998) Prescriptions, licences and evidence.
Psychiatric Bulletin 22, 680-4.
Herring C, et al. (2010) Off-label prescribing during pregnancy
in the UK: an analysis of 18 000 prescriptions in Liverpool
Women’s Hospital. International Journal of Pharmacy Practice
18, 226-9.
Hill P (2005) Off licence and off label prescribing in children:
litigation fears for physicians. Archives of Disease in
Childhood 90, i17-i8.
Iglehart J K (2009) Finding money for health care reform—
rooting out waste, fraud, and abuse. New England Journal of
Medicine 361, 229-31.
Jackson T & Kirkpatrick L (2011) Age related macular
degeneration: Cost comparison of ranibizumab and
bevacizumab. BMJ 343.
Jacobson P D & Parmet W E (2007) A New Era of
Unapproved Drugs. JAMA: the journal of the American
Medical Association 297, 205-8.
Johnston A, Pugatch M and Taylor D (2013) Clinical Trials and
Data Transparency – The Public Interest Case.
Finnegan G (2011) Into the eye of a storm. URL http://www.
medicalindependent.ie/4684/into_the_eye_of_a_storm.
Jonsson B (2009) Being NICE is not the problem! European
Journal of Cancer 45, 1100-2.
Frost J, et al. (2011) Patient-reported outcomes as a source
of evidence in off-label prescribing: analysis of data from
PatientsLikeMe. Journal of medical Internet research 13.
Kaiser P K, et al. (2012) Balancing risk in ophthalmic
prescribing: assessing the safety of anti-VEGF therapies and
the risks associated with unlicensed medicines. Graefe’s
Archive for Clinical and Experimental Ophthalmology 250,
1563-71.
Gazarian M, et al. (2006) Off-label use of medicines:
consensus recommendations for evaluating appropriateness.
Medical Journal of Australia 185, 544.
Gillick M R (2009) Controlling off-label medication use. Annals
of Internal Medicine 150, 344-7.
GMC G M C (2013) Prescribing guidance: prescribing
unlicensed medicines.. URL http://www.gmc-uk.org/
guidance/ethical_guidance/14327.asp.
18
Kaltenthaler E C, et al. (2012) A qualitative study of
manufacturers’ submissions to the UK NICE single technology
appraisal process. BMJ Open 2.
Kelly J B & Makkar H S (2012) Ethics in pediatric dermatology.
Clinics in Dermatology 30, 471-5.
Kelton E (2013) UK support for Glaxo but none for
whistleblowers? URL http://www.forbes.com/sites/
erikakelton/2013/12/26/uk-support-for-glaxo-but-none-forwhistleblowers/.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
Kesselheim A S (2010) Using market-exclusivity incentives to
promote pharmaceutical innovation. New England Journal of
Medicine 363, 1855-62.
Kesselheim A S, et al. (2006) The rise and fall of Natrecor for
congestive heart failure: implications for drug policy. Health
Affairs 25, 1095-102.
Kesselheim A S, et al. (2011) Strategies and practices in
off-label marketing of pharmaceuticals: a retrospective
analysis of whistleblower complaints. PLoS Med 8,
e1000431.
Kesselheim A S & Solomon D H (2010) Incentives for drug
development—the curious case of colchicine. New England
Journal of Medicine 362, 2045-7.
Kesselheim A S, et al. (2010) Whistle-blowers’ experiences in
fraud litigation against pharmaceutical companies. New
England Journal of Medicine 362, 1832-9.
Killick J R M (2012) The European Court affirms that public
safety comes first: financial considerations cannot justify the
placing on the market of unlicensed medicines.. URL http://
www.whitecase.com/articles-07172012/#.Ur3EvPS3M1M.
Kusel J & Wong G (2012) NI2 The Use of Off-Label
Comparators in Nice Appraisals – An Indirect Endorsement?
Value in Health 15, A278.
Kusel J, et al. (2013) The Use of Off-Label Comparators in
Nice Appraisals – An Indirect Endorsement? Unpublished.
Lenk C, et al. (2009) Off-label, off-limits? Parental awareness
and attitudes towards off-label use in paediatrics. European
Journal of Pediatrics 168, 1473-8.
Leonard S, et al. To what extent does advice from the SMC
agree with that published by NICE? URL http://www.
costellomedical.com/downloads/ISPOR_Madrid_Poster_
PHP123.pdf.
Littlejohns P, et al. (2009) 10 years of NICE: still growing and
still controversial. Lancet Oncol 10, 417-24.
Lundeby-Grepstad M, et al. (2014) Patients’ needs, medicines
innovation and the global public’s interests.
Mann R (1988) From mithridatium to modern medicine: the
management of drug safety. Journal of the Royal Society of
Medicine 81, 725.
Mullard A (2011) Mediator scandal rocks French medical
community. The Lancet 377, 890-2.
Mullins C D, et al. (2012) Recommendations for clinical trials
of off-label drugs used to treat advanced-stage cancer.
Journal of Clinical Oncology 30, 661-6.
Murray M (2014) Personal Communication.
Natz A & Sude O (2013) WORLD VIEW BLOG Austerity driven
off label prescribing must stop. URL http://www.
scripintelligence.com/home/WORLD-VIEW-BLOG-Austeritydriven-off-label-prescribing-must-stop-344674.
NHS Bournemouth and Poole and NHS Dorset (2013)
Commissioning statement on the use of amifampridine
(Firdapse) in Lambers-Eaton myesthenic syndrome. URL
http://www.dorsetccg.nhs.uk/Downloads/aboutus/medicinesmanagement/Other%20Guidelines/amifampridine%20
commissioning%20statement.pdf.
NICE (2007) Intrapartum care. Care of healthy women and
their babies during childbirth.. URL http://www.nice.org.uk/
guidance/CG55/NICEGuidance.
NICE (2008) Social values judgement paper. URL http://www.
nice.org.uk/media/C18/30/SVJ2PUBLICATION2008.pdf.
NICE (2010) Neuropathic pain. The pharmacological
managment of neuropathic pain in adults in non-specialist
settings. URL http://www.nice.org.uk/nicemedia/
live/12948/58253/58253.pdf.
NICE (2011a) Aripiprazole for schizophrenia in people aged
15 to 17 years. URL http://www.nice.org.uk/guidance/TA213.
NICE (2011b) Generalised anxiety disorder and panic disorder
(with or without agoraphobia) in adults. URL http://guidance.
nice.org.uk/CG113/NICEGuidance/pdf/English.
NICE (2013a) CG173 Neuropathic pain – pharmacological
management: The pharmacological management of
neuropathic pain in adults in non-specialist settings
NICE (2013b) Guide to the methods of technology appraisal.
Nicholl D J, et al. (2010) Open letter to prime minister David
Cameron and health secretary Andrew Lansley. BMJ 341.
Novac N (2013) Challenges and opportunities of drug
repositioning. Trends in Pharmacological Sciences.
Martin D (2010) Hospitals are forced to use unlicensed
medicines to save millions. URL http://www.dailymail.co.uk/
health/article-1315441/Hospitals-forced-use-unlicensedmedicines-save-millions.html.
O’Donnell P (2010) EMA chief warns against efforts to cut
cost of drugs. URL http://www.europeanvoice.com/article/
imported/ema-chief-warns-against-efforts-to-cut-cost-ofdrugs/68356.aspx.
Mason A, et al. (2010) Comparison of anticancer drug
coverage decisions in the United States and United Kingdom:
does the evidence support the rhetoric? Journal of Clinical
Oncology 28, 3234-8.
Penn R G (1979) The state control of medicines: the first 3000
years. British Journal of Clinical Pharmacology 8, 293-305.
Mason A R & Drummond M F (2009) Public funding of new
cancer drugs: Is NICE getting nastier? European Journal of
Cancer 45, 1188-92.
Pennington M, et al. (2013) Cemented, cementless, and
hybrid prostheses for total hip replacement: cost effectiveness
analysis. BMJ 346.
Perrone F, et al. (2012) Tackling Off-Label Use of Anticancer
Drugs. Journal of Clinical Oncology 30, 2800.
MHRA (2009) Off-label or unlicensed use of medicines:
prescribers’ responsibilities. URL http://www.mhra.gov.uk/
Safetyinformation/DrugSafetyUpdate/CON087990.
Pollack A (2007) Court rejects right to use drugs being tested.
URL http://www.nytimes.com/2007/08/08/health/08cancer.
html?_r=2&hp&oref=slogin&.
MHRA (2013) The supply of unlicensed medicinal products for
individual patients. URL http://www.mhra.gov.uk/
Howweregulate/Medicines/Doesmyproductneedalicence/
Medicinesthatdonotneedalicence/index.htm.
Pulse (2012a) Gps face clampdown on off label prescribing
after pharma company challenge. URL http://www.
pulsetoday.co.uk/gps-face-clampdown-on-off-labelprescribing-after-pharma-company-challenge/13814287.
article#.UrR2OvS3M1M.
Molyneux C & Bogaert P (2010) The need for informed
consent in off-label use in the EU. Regulatory Affairs Pharma
November, 13-6.
Mudiwa L (2012) Getting the best treatment possible for your
patients. URL http://www.imt.ie/clinical/2012/06/getting-thebest-treatment-possible-for-your-patients.html.
Pulse (2012b) The pharma industry must not dictate GMC
drug policy.. URL http://www.pulsetoday.co.uk/views/
editorial/the-pharma-industry-must-not-dictate-gmc-drugpolicy/13814311.article#.UrR3rvS3M1M.
Licensed to Cure? Public and patient interests relating to the use of
unlicensed products as comparators in cost effectiveness appraisals of licensed medicines
19
Raftery J & Powell J (2013) Health Technology Assessment in
the UK. The Lancet 382, 1278-85.
Skegg D & Doll R (1977) The case for recording events in
clinical trials. British Medical Journal 2, 1523.
Rägo L & Santoso B (2008) Drug regulation: history, present
and future. Drug Benefits and Risks: International Textbook of
Clinical Pharmacology, revised 2nd edition.
South Central Priorities Committees (2012) Amifampridine
(Firdapse) for Lambert-Eaton myasthenic syndrome (LEMS).
URL http://www.sph.nhs.uk/ebc/sph-files/ship-policies/
SHIP%20Policy%20143%20-%20Amifampridine%20for%20
LEMS.pdf.
Rawlins M, et al. (2010) Pharmacoeconomics: NICE’s
approach to decision-making. British Journal of Clinical
Pharmacology 70, 346-9.
Rawlins M D (2012) Crossing the fourth hurdle. British Journal
of Clinical Pharmacology 73, 855-60.
RCPCH (2010) The use of unlicensed medicines or licensed
medicines for unlicensed applications in paediatric practice..
URL http://www.rcpch.ac.uk/system/files/protected/page/
RCPCH%20Revised%20Statement%20on%20
Unlicensed%20Medicines%20October%202010%20FINAL.
pdf.
RNIB (2012a) Consultation response [to] NICE consultation:
bevacizamab as acomparator in the appraisal of
ranibizumbab for the treatment of macular oedema caused by
retinal vein occlusion.. URL www.nice.org.uk/nicemedia/
live/13040/63559/63559.pdf.
RNIB (2012b) Written evidence from Royal National Institute
of Blind People (NICE 44) to the House of Commons Health
Committee.. URL www.publicationsparliament.uk/pa/
cm201213/cmselect/cmhealth/782/782vw39.htm.
Routledge P (1998) 150 years of pharmacovigilance. The
Lancet 351, 1200-1.
Royal College of Psychiatrists (2007) Use of licensed
medicines for unlicensed applications in psychiatric practice.
College Report CR142.
Ruble J (2012) Off-label prescribing of medications for pain:
maintaining optimal care at an intersection of law, public
policy, and ethics. Journal of pain and palliative care
pharmacotherapy 26, 146-52.
Russell R (2011) Bisphosphonates: The first 40 years. Bone
49, 2-19.
Sanghavi D M (2013) The pills of last resort. URL http://
mobile.nytimes.com/2013/11/03/magazine/how-dyingpatients-get-access-to-experimental-drugs.
html?from=magazine.
Scottish Medicines Consortium (2012) Advice on
amifampridine phosphate Firdapse. URL http://www.
scottishmedicines.org.uk/files/advice/amifampridine_
phosphate_Firdapse_FINAL_July_2012_for_website.pdf.
Silverman E (2010) A battle over orphan drug pricing in the
UK. URL http://www.pharmalive.com/battle-over-orphandrug-pricing-uk.
Stafford R S (2008) Regulating Off-Label Drug Use —
Rethinking the Role of the FDA. New England Journal of
Medicine 358, 1427-9.
Stuart B & Wild C (2014) World Cancer Report 2014. IARC,
Lyon.
Sugarman P, et al. (2013) Off-licence prescribing and
regulation in psychiatry: current challenges require a new
model of governance. Therapeutic Advances in
Psychopharmacology.
Taylor L (2012a) GMC postpones plans to ease off-label
Rxing. URL http://www.pharmatimes.com/article/12-05-08/
GMC_postpones_plans_to_ease_off-label_Rxing.aspx.
Taylor L (2012b) PCT cluster backs down in Wet AMD drugs
row. URL http://www.pharmatimes.com/article/12-07-31/
PCT_cluster_backs_down_in_wet_AMD_drugs_row.aspx.
Thum-Bonanno S, et al. (2012) From making medicines to
optimising outcomes: The evolution of a profession 19122012.
Tomlin S (2011) Medicines tailored for children—the
introduction of buccal midazolam. Pharmaceutical Journal
287, 161.
Wagstaff A (2009) Health rationing in Europe: can cancer get
a fair hearing? Cancer, 25.
Whitfield K, et al. (2010) Compassionate use of interventions:
results of a European Clinical Research Infrastructures
Network (ECRIN) survey of ten European countries. Trials 11,
104.
Wikipedia (2012) List of off-label promotion pharmaceutical
settlements. URL http://en.wikipedia.org/wiki/List_of_offlabel_promotion_pharmaceutical_settlements.
Wiktorowicz M, et al. (2012) Pharmacovigilance in Europe and
North America: Divergent approaches. Social Science and
Medicine 75, 165-70.
Williams A (1997) Intergenerational equity: An exploration of
the ‘Fair Innings’ argument. Health Economics 6, 117-32.
Wilson D (2011) Glaxo settles cases with US for $3 billion.
New York Times, B1.
Wright O (2012) Prescribe cheaper drugs, GPs told. URL
http://www.independent.co.uk/news/uk/home-news/
prescribe-cheaper-drugs-gps-told-8433635.html
This report was researched and written by David Taylor, Tina Craig and Jennifer Gill. It was commissioned by the European Medicines
Group (EMG), which has 17 research-based European pharmaceutical sector company members. EMG members Bayer and Novartis
provided the majority of the funding to support the development of the publication. The research methods used were determined by
the authors and editorial control was exercised by Professor Taylor, who is accountable for all aspects of this document’s content.
Copyright UCL School of Pharmacy, March 2014 ISBN 978-0-902936-30-0 Price £7.50
Design & print: www.intertype.co.uk