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How NICE may be outflanked
R E Ferner and Sarah E McDowell
BMJ 2006;332;1268-1271
doi:10.1136/bmj.332.7552.1268
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References
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Analysis and comment
were upheld, five resulted in relatively minor changes
in the wording of the guidance. But five decisions
(interferon beta in multiple sclerosis, drugs for colorectal cancer, flu antivirals, growth hormone in adults, and
renal immunosupression in adults) were referred back
to the appraisal committee for further appraisal. The
appeals process has required NICE to show that it has
been comprehensive in its examination of the evidence
and consistent in its treatment of each topic.
1
Discussion
5
At its current rate of appraisal—around 20 a
year—NICE can cover only a minority of new and
existing treatments. This led to announcements in late
2005 of a more rapid review process.23 However, a
more rapid process is likely to be considerably less
intensive. The appraisal of drug treatments for
multiple sclerosis, for example, took much of NICE’s
first two years, with 338 documents listed on its website.
It eventually recommended against use of interferon
beta and glatiramer acetate because of their high cost
per QALY. Despite considerable effort, including additional research, NICE was unable to identify a
subgroup of patients in whom these drugs might have
a more acceptable level of cost effectiveness. The fact
that the government then intervened with a special
purchase scheme based on a cost per QALY gained of
£36 00021 indicated that the government thought this
was an acceptable level, at least for these drugs.
Overall NICE must be judged to have succeeded in
surviving some controversial decisions. Its appeal
system has imposed consistency and has so far
prevented appellants proceeding to legal challenge.
Although clinicians have understandably feared
blanket restrictions, these have been fairly rare. NICE
continues to be best characterised not by saying no, but
by saying yes but . . .
6
7
Contributors and sources: JR is a health economist who has
contributed to seven technology assessments for NICE.
Competing interests: None declared.
2
3
4
I thank Amanda Burls, Andy Clegg, Rumona Dickson, Ruairidh
Milne, Alec Miners, Mark Sculpher, Ken Stein, Rod Taylor, and
Tom Walley for help with classification of NICE guidance and
Carey Hendron for administrative help.
8
9
10
11
12
13
14
15
16
17
18
19
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21
22
23
Ham C, Robert G. Conclusions. In: Reasonable rationing. International experience of priority setting in health care. Milton Keynes: Open University
Press, 2003:141-56.
Duckett SJ. Drug policy down under: Australia’s pharmaceutical benefits
scheme. Health Care Financing Review 2004;25(3):55-67.
Porter RJ, Mulder RT. PHARMAC and availability of pharmaceuticals. N
Z Med 2002;115:274-5.
Corvari R, King D, Sanidas M. Canada: pharmaceutical pricing and
reimbursement. London: London School of Economics, 2005.
Stiftung B. Centre for quality in medicine: from policy paper to draft bill. Westphalia: Health Policy Monitor, 2004.
French medicine. The price of popping pills. Economist 2004 May15:40.
House of Commons Health Committee. Review of the National Institute for
Clinical Excellence. London: Stationery Office, 2002.
Hill S, Garattini S, van Loenhout J, O’Brien B, de Joncheere K. Technology
appraisal programme of the National Institute for Clinical Excellence: a review
by the WHO. London: NICE, 2003.
Robert G. The United Kingdom. In: Ham C, Robert G, eds. Reasonable
rationing. International experience of priority setting in health care. Milton
Keynes: Open University Press, 2003:64-93.
Newdick C. Who should we treat? Rights, rationing and resources in the NHS.
2nd ed. Oxford: Oxford University Press, 2005.
Raftery J. NICE: faster access to modern treatments? Analysis of guidance
on health technologies. BMJ 2001;323:1300-3.
Devlin N, Parkin D. Does NICE have a cost effectiveness threshold and
what other factors influence its decisions? A binary choice analysis. Health
Economics 2004;13:437-52.
Towse A, Devlin N, Pritchard C, eds. Cost effectiveness thresholds: economic
and ethical issues. London: Office of Health Economics, King’s Fund, 2002.
Miners AH, Garau M, Fidan D, Fischer AJ. Comparing estimates of cost
effectiveness submitted to the National Institute for Clinical Excellence
(NICE) by different organisations: retrospective study. BMJ
2005;330:65-8.
Devlin N, Parkin D. Does NICE have a cost effectiveness threshold and
what other factors influence its decisions? A binary choice analysis. Health
Economics 2004;13:437-52.
National Institute for Clinical Excellence. Guide to the methods of technology
appraisal. London: NICE, 2004.
National Institute for Clinical Excellence. Guidance on the use of riluzole for
motor neurone disease. London: NICE, 2001.
National Institute for Clinical Excellence. Guidance on the use of
trastuzumab for the treatment of advanced breast cancer. London: NICE, 2002.
National Institute for Clinical Excellence. Technology appraisal guidance No
50: the use of imatinib for chronic myeloid leukemia. London: NICE, 2002.
National Institute for Clinical Excellence. Technology appraisal guidance No
70: use of imatinib for chronic myeloid leukemia. London: NICE, 2003.
Department of Health. Cost effective provision of disease modifying
therapies for people with multiple sclerosis. Health Service Circular HSC
2002/004.
Hadhorn D. Setting health care priorities in Oregon. Cost effectiveness
meets the rule of rescue. JAMA 1991;265:2218-25.
National Institute for Clinical Excellence. NICE to issue faster drugs
guidance to NHS. London: NICE, 2005.
(Accepted 23 March 2006)
How NICE may be outflanked
R E Ferner, Sarah E McDowell
West Midlands
Centre for Adverse
Drug Reaction
Reporting, City
Hospital,
Birmingham
B18 7QH
R E Ferner
director
Sarah E McDowell
research officer
Correspondence to:
R E Ferner
r.e.ferner@
bham.ac.uk
BMJ 2006;332:1268–71
We argued a decade ago that the NHS should not have
to pay for new drugs unless they are at least as good as
older ones, nor for expensive drugs whose benefits are
uncertain.1 Since then, the National Institute for Health
and Clinical Excellence (NICE) has been created. NICE
appraises technologies that are available to the NHS
and recommends whether they should be used
unreservedly, with restrictions, or not at all.2 Part of its
remit is to ensure equity, but equity is not in everyone’s
interests. Here, we consider how individuals or groups
with specific interests may seek to outflank NICE.
Individual benefit or common good?
When many people share common resources, it is
rational for each individual to increase personal use of
the resources. But if all individuals do this, the
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resources are overexploited and eventually everyone
will be ruined. This is termed the tragedy of commons.3
The NHS is a common resource. A patient acts rationally in seeking an expensive treatment that produces a
benefit (even if small), because the cost falls almost
entirely on others. But the NHS cannot support
overexploitation indefinitely. It already spends £10.3bn
(€15bn; $19bn) a year on drugs, and costs are rising
rapidly.w1 One way to avoid overexploitation is to
appoint a guardian to administer the commons. NICE
plays this role but faces many challenges.
References w1-w36 are on bmj.com
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Analysis and comment
Appraisal process
NICE examines the value of drugs only when it is
invited to do so by the Department of Health and
Welsh Assembly, so it may never review some
important aspects of therapeutics. The process is complex, involves many interested parties (stakeholders),
and takes around two years to complete.w2 The delays
between the initial suggestion and the final determination can allow patterns of treatment of uncertain cost
effectiveness to become established. The longer the
patterns persist, the harder they become to reverse.
The use of verteporfin in treating age related macular
degeneration is a case in point.4 Further treatments
were licensed during the time NICE took to appraise
the evidence and rendered its guidance outdated.w3
NICE clearly appreciates the need to provide
thorough analysis in good time. It now aims to
appraise a drug for a specific indication in about 40
weeks. Appraisal may begin before regulatory approval
has been granted, so that NICE’s views are known
within a few months of the drug being licensed. Advice
is expected soon on the use of trastuzumab in early
breast cancer, for example, even though the manufacturer did not apply for a licence until February 2006.
Role of big pharma
Pharmaceutical companies spend over $800m to
develop and license a new drug,5 so they are
understandably interested in the financial returns. An
obvious insurance against loss is to produce a drug that
is clearly beneficial and whose costs are proportionate.
Even if a new drug offers only slight benefits at an
inflated cost, a company may be able to persuade doctors or patients of its value by marketing. It can then
hope for sales independent of guidance from NICE or
other expert bodies. Companies can also sell drugs by
relabelling normal phenomena such as male pattern
baldness and social phobia as diseases that then merit
drug treatment.6
The promotion of trastuzumab (Herceptin) shows
how companies raise awareness of new drugs. Marketing was muted at first, as specialists learnt of pilot studies in patients with advanced disease.w4 A paper
reporting an early trial in a wide circulation general
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medical journal amplified the signal.w5 The paper was
accompanied by an enthusiastic press release,w6
encouraging medical correspondents to spread the
word to the wider public.w7 These strategies mean
people become attuned to the company message long
before licensing.
The manufacturer or sponsor of a product has a
key role in the appraisal process through the
submission of data to NICE’s evidence review group.
The review group no doubt critically assesses the
industry submissions. However, published company
data contain inherent biases. Industry funded randomised trials are more likely to favour the treatment
under test,7 and authors are more likely to be positive
in their conclusions if a randomised trial is funded by a
for-profit organisation.8 Published economic evaluations of cancer drugs sponsored by drug companies
are also less likely to report unfavourable qualitative
conclusions.9
One reason for this bias could be that companies
fund the trials that they think are most likely to give
positive results, but other explanations are possible.
Conscious or unconscious optimism of those most
interested in a treatment’s success could colour the
judgment of study authors. Certainly, expected
cost-utility can vary greatly from one study to another.
In the case of photodynamic therapy, industry
estimated the cost of averting two years of blindness as
£70 000, whereas academic analysis suggested costs
between £150 000 and £300 000.w8
Companies also harness the media to support their
views in battles with NICE. If NICE gives restrictive
guidance, drug companies issue press releases
decrying the judgment.w9-w11 Pfizer described the recent
decision not to recommend inhaled insulin as
“perverse,”w10 and Link Pharmaceuticals claimed NICE
was denying “potentially life-prolonging treatments” to
patients with brain tumours.w9
Patients and patient groups
Patients may wish to have treatments that NICE has yet
to pronounce on or has recommended against. Patient
groups share a common interest with drug companies
in promoting access to specific treatments that others
will pay for, and so they provide a route for companies
to influence the perceptions of their drugs at a
distance.10 As Jo Spink, a public relations professional,
explains, “Patients are a powerful force and can
highlight the clinical, societal and quality of life benefits
of a treatment far more passionately than any press
release ever could.”w12
Patient groups have been described as conduits for
drug companies to promote their products11 and as
“ground troops” to be used to lobby governments for
increased access to new drugs.w13 A recent survey found
that 76% of patient groups based in the European
Union received support from drug companies,
although how much they received was unclear.w14
Groups campaigning for NICE to approve specific
drugs often have declared corporate relations with
pharmaceutical companies.w15-w17 Financial support
from a drug company may not compromise a patient
group’s independence, but companies are not motivated by altruism, and the House of Commons Health
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Analysis and comment
Select Committee has advised that measures be taken
to limit the influence of industry on patient groups.11
Patient groups often object strongly if NICE’s
preliminary recommendations are restrictive. Vocal
campaigns preceded changes in advice on treatment
for Alzheimer’s diseasew18-w20 and osteoporosisw21 and
patient groups are seeking to overturn NICE’s preliminary, unfavourable, view of inhaled insulin.w22
The influence of patients and patient groups can be
seen even before a NICE appraisal has been
commissioned. Trastuzumab has yet to be licensed for
use in early breast cancer, its longer term efficacy is
uncertain, and its propensity to cause myocardial
damage in patients who have taken anthracyclines is
worrying. The cost of treating a patient with
trastuzumab in the United Kingdom is about the same
as the average annual income. Patients have campaigned successfully to place trastuzumab at the
forefront of public and political consciousness.w23 w24
This has led to the feeling that the licensing and NICE
approval of trastuzumab for early stage cancer is a
foregone conclusion. This is a sentiment expressed by
the chief executive officer for Breakthrough Cancer
Care: “The fast track appraisal of drugs by NICE is to
be welcomed but we need to ensure that once
approved, guidance is implemented fully and that
cancer patients receive the drugs recommended.”w25
Media influence
Dying patients denied life saving drugs make compelling copy.w26 Better still, when heartless bureaucrats are
persuaded to change their minds under media
pressure, the media can take the credit for saving the
patient.w27 The Manchester Evening News even received
an award for its campaign over trastuzumab.w28 Stories
of wonder drugs, carefully encapsulated in press
releases, can make useful copy even in the absence of
human interest. And careful deployment of celebrities
by patient groups can ensure media exposure for
both.w29 Newspaper columnists such as Clare Rayner
and Thomas Stuttaford have also launched populist
attacks on NICE rationing.w30-w33
Politicians
Many members of parliament are ready to espouse
popular causes such as supporting patients with cancer
or crippling diseases. Tabling questions in parliament is
an effective way to do this. The House of Commons
question book lists 84 questions on trastuzumab, 56 on
donepezil, and 188 on interferon beta, but only two on
ciprofloxacin, and none on penicillin or prednisolone.w34
Ministerial interventions may complicate matters.
While he was a health minister, Stephen Ladyman
commented on preliminary guidance that recommended the withdrawal of drugs for Alzheimer’s
disease. He stated that “they [NICE] have to look at the
wider impact of this decision. It may well be that once
they have looked at the extra evidence, they will come
to a different decision.”w35 Even before trastuzumab has
been licensed for treatment of early breast cancer,
Patricia Hewitt, the secretary of state for health, has
stated that primary care trusts “should not refuse to
fund Herceptin [trastuzumab] solely on the grounds of
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Summary points
The work of NICE is critically important to the
rational distribution of NHS funds
Patients and drug companies seek to influence
the decisions both during and after appraisal
The government risks undermining NICE by
making decisions before guidance is published
Appraisal of treatments needs to be insulated
from external pressure
its cost.”w36 She has instituted genotyping of all breast
cancers, so fostering expectations of trastuzumab treatment directed at the 20% of tumours that are HER-2
positive.12
Practising clinicians
Published NICE guidelines may not be implemented
as intended.13 Abacus International found that 12 of 28
NICE appraisals were underimplemented and four
were overimplemented.14 Since many NICE decisions
are based on fine and perhaps generous judgments of
cost-utility, overimplementation is likely to be expensive.15
Pressured decisions
Opportunities exist for distortion long before the
NICE appraisal process begins. They continue after the
process has begun and persist after preliminary
findings are published. Even when the final NICE
determination recommends abandonment of or
restriction in the use of a treatment, interested parties
may make determined efforts to by-pass NICE’s ruling.
Audits suggest that many of NICE’s recommendations
are not implemented completely.
It is easy to see why patients, whose illnesses
provide strong motivation to obtain a share of NHS
resources, wish their voices to be heard. It is also clear
that companies, which have to make a profit, will seek
what advantage they can. Less easily understood is the
way that politicians seem to undermine NICE. The
government set up NICE as an independent body, and
so ministers should be absolutely scrupulous in allowing it to function independently. By making, or appearing to make, decisions before NICE has pronounced
and for reasons of political expediency, some
politicians may be subverting the process. It will be a
test of NICE’s resolve to see that treatments are cost
effective when they analyse the data on trastuzumab in
early breast cancer.
NICE should ensure that the funding available for
drugs in the NHS is spent in a way that best serves
patients. But in the ideal world the appraisal process
would be insulated, and seen to be insulated, from
external financial, political, and emotional pressures.
Competing interests: REF was senior registrar to the current
chair of NICE.
Funding: SEMcD was supported by the Antidote Trust Fund of
the Sandwell and West Birmingham Hospitals NHS Trust.
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Analysis and comment
Contributors and sources: REF is a consultant physician and
clinical pharmacologist and chairs the drug and therapeutics
committee of a large NHS Trust. SEMcD is a health scientist
interested in prescribing and adverse drug reactions. Both
believe that rational therapeutics is important. REF wrote the
first draft and will act as guarantor. SEMcD participated in the
research for the paper and contributed to the writing.
1
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Raftery J. NICE work: review of NICE’s recommendations, 1999-2005.
BMJ 2006;332:1266-8.
Hardin G. The tragedy of the commons. Science 1968;162:1243-8.
Foot B, Foy R, Chakravarthy U, Wormald R. Increasing use of a new
health technology during the wait for NICE guidance: findings from the
third national tracker survey of photodynamic therapy. J Public Health
(Oxf) 2004;26:52-5.
DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new
estimates of drug development costs. J Health Econ 2003;22:151-85.
Moynihan R, Heath I, Henry D. Selling sickness: the pharmaceutical
industry and disease mongering. BMJ 2002;324:886-91.
Bhandari M, Busse JW, Jackowski D, Montori VM, Schunemann H,
Sprague S, et al. Association between industry funding and statistically
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significant pro-industry findings in medical and surgical randomized
trials. CMAJ 2004;170:477-80.
Kjaergard LL, Als-Nielsen B. Association between competing interests
and authors’ conclusions: epidemiological study of randomised clinical
trials published in the BMJ. BMJ 2002;325:249-52.
Friedberg M, Saffran B, Stinson TJ, Nelson W, Bennett CL. Evaluation of
conflict of interest in economic analyses of new drugs used in oncology.
JAMA 1999;282:1453-7.
Herxheimer A. Relationships between the pharmaceutical industry and
patients’ organisations. BMJ 2003;326:1208-10.
House of Commons Health Committee. The influence of the pharmaceutical industry. Fourth report of session 2004-2005. London: Stationery Office,
2005.
Department of Health. Hewitt fast-tracks cancer drug to save 1000 lives.
2005. www.dh.gov.uk (search for: 0339).
Sheldon TA, Cullum N, Dawson D, Lankshear A, Lowson K, Watt I, et al.
What’s the evidence that NICE guidance has been implemented? Results
from a national evaluation using time series analysis, audit of patients’
notes, and interviews. BMJ 2004;329:999-1004.
Abacus International. NICE guidance implementation tracking data
sources,
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and
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www.nice.org.uk/pdf/
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Maynard A, Street A. Seven years of feast, seven years of famine: boom to
bust in the NHS? BMJ 2006;332;906-8.
When I use a word
Nauseated/nauseous
I am often told that a patient is nauseous, only to find
that he or she is actually nauseated, not nauseous at all,
or at least not what I mean by nauseous.
The word nausea comes from the Greek nausia or
nautia, which originally meant seasickness (Greek
naus = ship). In Latin nauseare meant to make sick;
nauseated (from the supine form nauseatum) therefore
means made to feel sick (verb transitive) or feeling sick
(adjective).
Now the suffix -osus in Latin meant full of or rich in.
And, although nauseosus could have meant feeling
sick or nauseated, it was actually used to mean causing
nausea. When nauseous came into English from the
Latin it first meant likely to feel sick (that is, squeamish)
or fastidious, but that meaning rapidly became
obsolete. At the same time nauseous was used in its
original Latin sense of causing nausea, and therefore
smelling or tasting unpleasant and (figuratively)
loathsome or disgusting. And that meaning persisted
until about the middle of the 20th century.
However, Webster’s Third International Dictionary
(1961) gave two different meanings of nauseous: 1.
Affected with or inclined to nausea: nauseated. 2.
Causing or such as might be expected to cause nausea:
sickening, loathsome, disgusting. This distinction was
not made in Webster’s second (Webster’s New
International Dictionary), so presumably the new
meaning arose at some time between 1913 and 1961.
The distinction between nauseous and nauseated
was not discussed by Fowler in his Modern English
Usage (1926), nor by Ernest Gowers in his revision of
Fowler (1965), but it was discussed in Bob Burchfield’s
revision (1996; see also BMJ 2000;320:357), in which
he distinguished between British English and
American English usages. According to Burchfield, in
British English nauseated means feeling sick and
nauseous means disgusting, but in American English
nauseous has tended to replace nauseated, while
nauseating has replaced nauseous.
On the other hand, some US sources have
condemned the failure to observe the original
distinction between nauseous and nauseated. For
example, Wilson Follett, in his Modern American Usage
(1966), wrote: “When we have two adjectives, nauseous
BMJ VOLUME 332
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and nauseated, it should be clear that the first applies
to the substance that causes the state named in the
second. To call oneself nauseous, except in
self-depreciation, is to ignore the point of view of the
word.” And Strunk and White in The Elements of Style
(3rd edition, 1979) wrote: “Do not say ‘I feel nauseous’,
unless you are sure you have that effect on others.”
Nevertheless, by 1989 Webster’s Dictionary of English
Usage had gathered a large amount of evidence of the
widespread use of nauseous to mean nauseated: “Any
handbook that tells you that nauseous cannot mean
‘nauseated’ is out of touch with the contemporary [US]
language.”
Searching PubMed for examples of nauseous and
nauseated in the titles and abstracts of bioscience
publications, I have found only seven instances of
nauseous in UK publications, compared with 51
worldwide, and 97 instances of nauseated worldwide.
In one paper both were used: “The procedure had no
significant effect on cardiovascular variables in control
subjects or in subjects who were exposed to vestibular
stimulation but who were not nauseated by it. Those
subjects who felt nauseous showed a tachycardia and
forearm vasodilatation” (Cardiovascular Research
1982;16:610-2). This example is interesting in that it
shows the use of nauseated in the verbal sense and
nauseous, meaning nauseated, in the adjectival.
But I still think that, although several of my patients
are or become nauseated, sometimes because of drugs
that I give them, very few of them are really nauseous.
Jeff Aronson clinical pharmacologist, Oxford
([email protected])
We welcome articles up to 600 words on topics such as
A memorable patient, A paper that changed my practice, My
most unfortunate mistake, or any other piece conveying
instruction, pathos, or humour. Please submit the
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1271