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Articles
Evaluating promotional material from
industry: an evidence-based approach
In this article, the authors illustrate how the principles of information mastery, described in a previous article (PJ, 5 February, p148), may be used
to evaluate promotional material produced by the pharmaceutical industry
M
Scott Pegler is principal pharmacist and
medicines information manager at Swansea
NHS Trust
Jonathan Underhill is assistant director,
education and development, at the National
Prescribing Centre
Correspondence to Jonathan Underhill
(e-mail [email protected])
www.pjonline.com
should be noted and is neatly summarised by
the comment that “. . . then it won’t be seen
as the company pushing its product, it will be
seen as health education”.
Do not believe all you read and hear
Although much of the promotional information health care professionals receive from the
industry is based on good evidence, this is not
always the case. A study reviewed all advertisements for antihypertensives and lipidlowering drugs published in six Spanish medical journals in 1997.6 Of 125 references cited
to support advertisements, the authors of the
study were unable to retrieve 23 of the references from monographic works and nonpublished “data on file”. In 45 claims, the
promotional statement was not supported by
the reference, most frequently because the advertising slogan recommended the drug in a
patient group other than that assessed in the
cited study.
Furthermore, an analysis of the accuracy of
information provided by pharmaceutical representatives found that one in 10 statements —
all of which favoured their product — were at
odds with their company’s own literature.7
Importantly, only one in four health professionals was aware that the information provided by the drug representative was incorrect.
“Pharmaceutical reps”
The pharmaceutical industry employs over
8,000 pharmaceutical representatives to promote its products to approximately 60,000
NHS doctors.2 This equates to a ratio of one
full-time pharmaceutical representative to 7.5
doctors — a “teacher:student” ratio a school
could only dream of!
Pharmaceutical representatives are effective at packaging and delivering key messages
about their products. However, the “evidence” supporting such messages may be of
variable quality and so it is essential that
health professionals are able quickly to appraise such evidence and ensure its validity.
Will McIntyre/SPL
edicines are big business. The NHS
currently spends around £10bn a year
on pharmaceuticals, equating to
roughly £30m a day.1 This expenditure is increasing both in the UK and throughout the
world.Although a lot of resources are invested
in research and development, the pharmaceutical industry spends far more on marketing
and administration of its products (on average
around 35 per cent of sales) than on trying to
discover new ones.2
To put this into context, figures from the
US make interesting reading. For example, in
2000, Merck spent $161m advertising Vioxx
(rofecoxib). This was more than PepsiCo
spent advertising Pepsi ($125m) and
Anheuser-Busch spent advertising Budweiser
($146m) in the same period.3
The pharmaceutical industry employs various strategies to interact with health professionals. The method health professionals are
most familiar with is face-to-face visits from
pharmaceutical sales representatives. Many
less direct methods of drug promotion are
also used, such as direct mailing, advertising in
medical journals and newspapers, and sponsorship of medical conferences and products.
For a smaller proportion of health professionals, interaction with the industry may occur
through involvement in clinical trials or advisory groups.
A more subtle form of drug promotion is
raising public awareness of a disease through
campaigns in the general media or through
support of self-help groups (disease-awareness
campaigns).4 These are often sponsored by a
pharmaceutical company that markets (or is
about to launch) a product available to treat
the particular condition.Although companies
are not being able to advertise a prescription
only medicine (POM) direct to the public in
the UK, public awareness campaigns serve to
encourage both existing and potential patients to seek these new treatments.An excellent recent example of this was given in the
BMJ concerning the use of a testosterone
patch for female sexual dysfunction.5 In particular, the subtlety involved in this approach
Pharmaceutical representatives are
effective at delivering key messages
In our previous article (PJ, 5 February,
p148), readers were introduced to the “usefulness equation” as a way of evaluating medical information.8
Usefulness=
relevance x validity
time to locate and interpret information
When the usefulness equation is applied
to information provided by pharmaceutical
representatives, work (the time needed to locate and interpret the information) is low,
since the representative usually delivers the
information direct to the health professional,
often accompanied by food and other goodies (pens, pads, etc). However, as demonstrated by the earlier evidence, the relevance
and validity of the information often remains
uncertain. Some commonly misused shortcuts for choosing therapies are shown in
Panel 1.
Panel 1: Commonly misused shortcuts for choosing therapies9
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Newer is better
Experts know best
If there is a mechanism for how the drug works, then it works
If my peers are using the therapy, then so should I
If the patient improves after the therapy is prescribed, then the therapy must have worked
If the manufacturer gives gifts, I should support them in return
5 March 2005 The Pharmaceutical Journal (Vol 274) 271
Articles
In order to determine the relevance and
validity of promotional material, a number of
factors need to be considered. A selection of
the most important and commonly seen factors are discussed below. Further sources of
information are given at the end of this article.
What sort of evidence is available?
Many claims made by the pharmaceutical industry, particularly for new drugs, are based
on the results of trials that use surrogate endpoints and give rise to disease-oriented evidence (DOE). Surrogate endpoints are
variables that are relatively easily measured in
trials and are used to predict a rare or distant
outcome of a therapeutic intervention, but in
themselves are not a direct measure of either
harm or clinical benefit. Surrogate endpoints
are commonly used in trials because the size,
duration and, therefore, cost of the trial can
be reduced.
For example, claims may be made that an
antibiotic provides “better penetration into
sputum” or the latest antihypertensive gives
“better 24-hour blood pressure control”.
Although these factors may be of interest, to
base or change clinical practice on the basis of
DOE is inappropriate and may even be dangerous (PJ, 5 February, p148). It often requires
a leap of faith to assume that these surrogate
markers of efficacy will translate into actual
clinical benefits for the patient when the drug
is used in practice.
Results from research studies that health
professionals (and their patients) should care
about are those that measure outcomes that
produce tangible benefits to patients and so
give rise to patient-oriented evidence that
matters (POEMs), eg, whether a patient
lives longer, suffers less pain or has an improved quality of life as a result of taking the
drug.
Consider the marketing of cyclooxygenase-2 inhibitors: much of the early advertising of these drugs focused on the finding that, compared with traditional
non-steroidal anti-inflammatory drugs, these
drugs caused fewer ulcers as detected via an
endoscope. This is disease-oriented evidence
(DOE) since these ulcers do not consistently
translate into pain or more serious ulcers, and
are not indicators of true harm, such as a perforation, symptomatic ulcer or a bleed (any of
which would be POEM). Indeed, once such
evidence was published, close scrutiny of the
two major trials for drugs in this class — rofecoxib (VIGOR)10 and celecoxib (CLASS)11
— showed these drugs produced an increased
risk of serious adverse effects compared with
traditional NSAIDs (a 1.5 per cent and 1.0
per cent absolute risk increase, respectively)
— a factor which was not always apparent
from reviews of these interventions or in their
promotional materials.12
Does trial population reflect real life?
Patients included in clinical trials are often
carefully selected, do not have co-morbidities
and their characteristics may not reflect the
272
The Pharmaceutical Journal (Vol 274) 5 March 2005
“typical” patient who will ultimately use the
drug in real life.
For example, a study from Canada
analysed the characteristics of patients enrolled into trials of NSAIDs and found that
only 2.1 per cent of subjects recruited were
aged 65 years or more, despite NSAIDs
being much more commonly used in the
elderly in practice.13 It is also extremely important to have evidence of the use of these
agents in the elderly since they are more
likely to experience an adverse effect compared with a younger, fitter population.
Another example to remember is that of antidepressants, where studies are often performed in highly selected hospital-based
populations. The applicability of these data
to patients seen in primary care is, therefore,
questionable.14
Choice of comparator drug and dose?
The choice of drug used for comparison or
the dose can influence the likely outcome of
a clinical trial. Researchers may use a comparator drug that is not generally regarded as
the standard therapy for a given condition or
choose a suboptimal dose of the comparator
drug.
For example, in the two largest studies of
meloxicam,15,16 a relatively low dose of
meloxicam (7.5mg daily) was used and one of
the studies used piroxicam as the comparator
agent.16 Piroxicam is widely considered to be
one of the NSAIDs with a greater tendency
to cause gastrointestinal toxicity.17 This has the
effect of minimising the risk of side effects
from meloxicam (by using a relatively low
dose) but potentially maximising the harms
seen in the comparator arm (by using one of
the more GI-toxic NSAIDs). In short, one
can question whether such studies are making
a fair comparison.
Relative risk vs absolute risk reduction?
Relative risk reductions always sound more
impressive than absolute risk reductions and
tend to be used in advertising material, particularly when describing the benefits of a
product. Many practitioners are confused by
these terms and it may be best explained in
terms of buying a lottery ticket. The chance
(“absolute risk”) of winning the lottery jackpot by buying one ticket is about 1 in 14 million. By buying two lottery tickets, the
chances (relative risk) of winning the jackpot
are doubled (ie, increased by 100 per cent)
but the absolute risk of winning is only
slightly higher at 2 in 14 million (or 1 in 7
million). Hence, even by doubling the relative
risk, the absolute risk is still extremely small
for rare events — like winning the lottery
jackpot.
An example of how the results of studies
are sometimes miscommunicated to others is
provided by the CURE (Clopidogrel in
Unstable Angina to Prevent Recurrent
Events) study.18 This study received much
publicity when first published and had a
website dedicated to the findings
(www.thecurestudy.com) containing a
PowerPoint presentation available for health
care professionals to download.
The results suggested that taking clopidogrel in combination with aspirin reduced the
risk of having subsequent cardiovascular
events compared with aspirin used alone.This
was consistently reported as equating to a 20
per cent relative risk reduction without reference to the absolute risk reduction produced
(actually a 2.1 per cent absolute risk reduction).19
The harms associated with the combination of clopidogrel with aspirin were also
highlighted in the results but were reported as
showing a 1 per cent increase in serious
bleeds in those taking the combination. This
is of course the absolute risk increase — the
relative risk increase in bleeds was 38 per
cent, but was not communicated in the findings in this way.
Clearly, this makes interpretation of the
clinical significance of the risks and benefits
of this intervention difficult without an appreciation of the differences between relative
and absolute risk. We are not suggesting that
this was an attempt at duplicity on the part of
the manufacturers, but it shows how results of
studies may be presented in an accurate way
while the implications of such results may be
misleading to the unwary.
One method often used to try to convey
a balanced report of the harms and benefits
of an intervention is the number needed to
treat (NNT) or the number needed to harm
(NNH). Here, the absolute risk differences
between the intervention and the control
groups are used to estimate the number of
people that need to be treated with an intervention to prevent (or cause) an event. In the
CURE study for example, the NNT to prevent one cardiovascular event was about 50,
while the NNH to cause a major bleed was
100. Put another way, if 100 people similar to
those in the study were to receive clopidogrel plus aspirin rather than aspirin alone,
two of them would have a cardiovascular
event prevented while one would have a
major bleed caused. The website
www.nntonline.net gives an excellent explanation of how this tool can be used to communicate the results of trials to others
effectively, including patients.
Statistical vs clinical significance?
Statistical significance and clinical significance
do not necessarily mean the same thing, and
caution is required when promotional material states the results of a study are “significant”. Statistical significance simply means
that the results were unlikely to have occurred
by chance. Whether a statistically significant
intervention is deemed clinically significant
will depend on the size of the effect being
measured and whether it provides any meaningful benefit to the patient. It is also determined by whether the intervention is
warranted or justified in routine practice.
For example, a Cochrane review into the
use of antibiotics to treat sore throat found
that those taking antibiotics endured symp-
www.pjonline.com
Articles
toms of headache, throat soreness and fever
for less time than those taking placebo.20
However, these differences equated to an average of one day half way through the illness,
with about 90 per cent of both treated and
untreated patients symptom-free by one
week.Although this result was statistically significant, the clinical significance of such an
intervention is questionable.
Other factors to consider
Health professionals should be aware of the
potential for publication bias. For a number of
reasons, studies showing positive differences
between interventions are more likely to be
published than those showing no difference or
inferiority of the study drug. Furthermore,
studies with positive findings can sometimes
lead to multiple publications, particularly in
multicentre trials.
These factors can lead to problems where
a meta-analysis is performed (where data
from small similar studies are combined to increase the “power” of the study so that
stronger conclusions may be drawn). Where
positive publication bias exists, results from
the trials showing a positive result are more
likely to be included, or one set of study participants may be included in the analysis
twice. This may lead to an overestimation of
treatment effects. The latter was seen in a
meta-analysis of trials of ondansetron for prevention and treatment of postoperative nausea and vomiting.21
It should also be remembered that clinical
trials are not like real life since patients in trials are generally more likely to be motivated
to remember to take their medicines and are
usually more intensively monitored than they
are in routine clinical practice. These factors
require consideration because trial results may
exaggerate the benefits of an intervention
that is simply not realistic or achievable for
the majority of patients when incorporated
into their busy daily lives.
Of course there are many other considerations to take into account when appraising clinical trials. Sources of further
information are given at the end of this article.
STEPS
So how can we attempt to walk through this
minefield? Use STEPS. The STEPS
acronym22 gives five simple and valid reasons
for consideration when deciding the benefits
and harms of one drug over another:
Safety If possible, determine safety from
real-life comparison studies since these will
better reflect the patient population that will
ultimately use the drug. Specifically, check for
adverse effects that would place patients at
significant risk, eg, cardiovascular events, liver
and renal toxicity, seizures and bone marrow
suppression.
Tolerability Tolerability will question
whether the drug produces effects that will
affect compliance. A more reliable indicator
www.pjonline.com
Panel 2: Using STEPS in
practice — deciding which
statin to use for a patient
drugs taken once a day is generally better
than for those requiring administration four
times a day), or the ease of use of a delivery
device.
The practical application of these five criteria can be seen in Panel 2.
Simvastatin vs rosuvastatin
How do we relate this to patient care?
Safety
■ Simvastatin — long-term safety record well
established with known and quantifiable risk
of adverse effects
■ Rosuvastatin — less well established
because rare but significant adverse effects
may still be undetermined due to less
widespread use compared with other statins
Tolerability
■ Probably similarly tolerated, profile better
established for simvastatin
Effectiveness
■ Simvastatin has evidence that it not only
produces a favourable cholesterol profile
but also reduces heart attacks, strokes,
death and other patient-oriented
outcomes
■ Rosuvastatin only shown to reduce LDLcholesterol and increase HDL-cholesterol
Price (as per Drug Tariff January 2005)
■ Simvastatin — £15.60 for 28 days at 40mg
per day
■ Rosuvastatin — £29.69 for 28 days at 20mg
per day
Simplicity
■ Both are taken once a day, no other relevant
differences
than trying to compare lists of side effects is
to compare dropout rates from clinical
trials.
Effectiveness Effectiveness is basically determined by asking the question: “Does the
drug work in the real world?”To help answer
this question, one should look for head-tohead trials that compare the new drug with
the current standard therapy used at a dose
that is known to be effective. (Note: comparing the relative response rates or the incidence of adverse effects of two drugs using
data from different trials may not give valid
comparisons if the populations studied were
different.)
Price Include all costs when making a comparison between a new drug and alternative
therapy. This may include the costs of additional visits to titrate doses or maybe the cost
of biochemical tests to monitor therapy.
Simplicity of use Think of the patient.
Factors that may be important in the simplicity of use include the availability of the
drug as a liquid formulation, the frequency
of administration (since compliance with
A similar set of criteria to consider when
making a prescribing decision was defined by
Nick Barber in 1995 in the BMJ:23
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Effectiveness
Safety
Cost
Patient factors
Although this framework is only rarely
used consciously, every single clinical decision
that is ever taken is a balance between four
factors, which have their roots in medical
ethics — beneficence, non-maleficence, justice and patient autonomy.
It is not enough merely to understand the
likely relative risks and benefits in a given
population. Health care professionals must be
skilled in relating and communicating this to
a patient in terms they can understand. This
also requires an appreciation of the fact that
patients or fellow health professionals may
not share the same values as you do — some
may be particularly risk averse, while others
may accept a much higher degree of risk set
against another potential benefit. Only then
are we likely to be able to allow patients to
reach informed decisions about their treatment plans.
Final thoughts . . .
By focusing on the points above and applying STEPS, health professionals have a simple and objective method to review quickly
the quality of information provided by the
pharmaceutical industry. When used in
combination with an effective method of
finding valid and relevant information, as
discussed in our previous article (PJ, 5
February, p148) health professionals will be
better placed to make an informed judgement regarding advertising claims. Health
professionals should insist on having sufficient information to substantiate any claims
made about products. For example, where
the benefits of a new drug appear to be
based on data derived from studies using
surrogate endpoints, health professionals
may wish to request further patientoriented evidence to justify these claims.
The pharmaceutical industry can undoubtedly be extremely helpful in highlighting and providing new and important
information to health professionals.
However, by adopting these simple techniques, health professionals will be able to
integrate their expertise with the wishes of
their patients and the best available evidence,
and so always ensure that they get the most
from their interactions with the pharmaceutical industry — while also effectively managing their information load.
5 March 2005 The Pharmaceutical Journal (Vol 274) 273
Articles
DECLARATION OF INTEREST Jonathan
Underhill is involved in the organisation of
two information mastery conferences being
run by the NPC in conjunction with the
founders of information mastery and
POEMs. Scott Pegler is the distributor for
InfoPOEM Inc in the UK and Ireland.
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Useful resources
■ No Free Lunch UK. www.nofreelunch-uk.org
■ National Electronic Library for Health (NeLH) gives access to
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Cochrane, Clinical Evidence, MeReC, Drug and Therapeutics
Bulletin, Bandolier, etc. www.nelh.nhs.uk
An Introduction to Information Mastery. www.poems.msu.
edu/InfoMastery
InfoPOEMS. www.infopoems.com
National Prescribing Centre. www.npc.nhs.uk
Clinical Evidence. www.clinicalevidence.org
Effective Health Care Bulletin. www.york.ac.uk/inst/crd
Cochrane Collaboration. www.cochrane.co.uk
National Institute for Clinical Excellence. www.nice.org.uk
United Kingdom Medicines Information. www.ukmi.nhs.uk
Centre for Evidence Based Medicine. www.cebm.net
CASP (Critical Appraisal Skills Programme). www.phru.nhs.
uk/casp/casp.htm
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