E-drug: Medicines, society, and industry
---------------------------------------------
Long message!
[Joe Collier and Ike Iheanacho open a 4 week series in the Lancet
providing a critique of the roles taken by the pharmaceutical
industry, particularly the transnational companies, within society.
The Lancet 'Commentary' is provided, followed by the full article for
those e-druggers who find it hard to access websites. Copied as
fair use. BS]
Lancet
Volume 360, Number 9343 02 November 2002
http://www.thelancet.com/journal/vol/iss/full/llan.360.9343.editorial_and_review.22976.1
[Long URL needs to be repaired. BS]
Commentary
Medicines, society, and industry
Medical journals, and this one is no exception, owe much to the
pharmaceutical industry. Not only is the pharmaceutical industry the
largest sponsor of medical research in some countries, and that
research generates the need for many journals, but industry also
contributes to journals' profits through reprint orders, sponsored
subscriptions or supplements, and display advertising. Without pharma
revenue many journals could not exist. Scanning the acknowledgments
and conflict of interest statements of any issue of The Lancet goes
some way to illustrating the extent to which research and individuals
are dependent on industry funding. And publication, of course, may
help to change prescribing habits, especially if in a prominent
widely read journal that generates press interest.
That there is a symbiotic relation between medical journals and the
pharmaceutical industry is clear, and both industries profit from
each other, but it is a relation that generates unease and is open to
abuse. Editors of medical journals should make decisions on content
based on public-health needs, their journal's readership, and the
medical community's needs, not on likely reprint revenues or
advertising potential. Separating decisions on content from
commercial influence is particularly important for medical journals
because it is patients' health that is directly affected by
prescribing practices--an outcome that some journal owners would
prefer to forget. The content of medical journals has to serve the
public's health over and above the needs of the pharmaceutical
industry or the journals' owners, but this is not an easy balance to
achieve.
The content of medical journals is just one example of the complex
relation between the pharmaceutical industry and society. The
industry, patients, doctors, editors and publishers, regulators, and
politicians are all driven by their own agendas and are subject to
various influences, some of which are extremely powerful. But at its
most basic level, the primary aim of providing medicines has to be to
improve the health of populations. Which disease in which population
is judged important to treat, who makes those decisions, how the
medicines are provided, and who profits from their provision, are
all, however, subject to influence from different sectors of society.
We aim to explore some of these agendas and influences on the
provision of medicines to society in a series of four commissioned
papers to run in consecutive weeks beginning today. We hope that the
four papers will provide a critique of the roles taken by the
pharmaceutical industry, particularly the transnational companies,
within society. We begin with how industry provides information to
sectors of society (this week's issue) and move on to how industry
interacts with governments, how it supplies medicines, and finally to
whom it is accountable. We aim to generate a wider discussion and
anticipate receiving much correspondence. We thank Professor Joe
Collier, from the Medicines Policy Unit, St George's Hospital Medical
School, London, UK, and editor of the Drug and Therapeutics Bulletin,
for his advice on the structure and content of this series.
Astrid James
The Lancet, London NW1 7BY, UK
----------------------------------------------------
Lancet. Volume 360, Number 9343 02 November 2002
The pharmaceutical industry as an informant
Joe Collier, Ike Iheanacho Lancet 2002; 360: 1405-09
Medicines Policy Unit, Department of Pharmacology and Clinical
Pharmacology, St George's Hospital Medical School, London SW17 0RE,
UK (Prof J Collier FRCP); and Consumers' Association, London NW1 4DF
(Prof J Collier, I Iheanacho MBBS)
Correspondence to: Prof Joe Collier, Medicines Policy Unit,
Department of Pharmacology, St George's Hospital Medical School,
London SW17 0RE, UK (e-mail:jcollier@sghms.ac.uk)
The pharmaceutical industry spends more time and resources on
generation, collation, and dissemination of medical information than
it does on production of medicines. This information is essential as
a resource for development of medicines, but is also needed to
satisfy licensing requirements, protect patents, promote sales, and
advise patients, prescribers, and dispensers. Such information is of
great commercial value, and most of it is confidential, protected by
regulations about intellectual property rights. Through their
generation and dissemination of information, transnational companies
can greatly influence clinical practice. Sometimes, their
commercially determined goals represent genuine advances in
health-care provision, but most often they are implicated in
excessive and costly production of information that is largely kept
secret, often duplicated, and can risk undermining the best interests
of patients and society.
Production of medicines is a data-rich business. Although the primary
function of drug companies is to develop and market drugs, these
companies spend more time and resources generating, gathering, and
disseminating information.1 These data are so important to the
business interests of companies that most are regarded as
commercially sensitive and remain confidential and protected by law.
In this article, we consider the role of industry as informant,
concentrating on the activities of transnational companies--ie, those
with a global rather than a national or regional customer
base--operating within the legislative frameworks of industrialised
countries. However, such a focus offers a limited perspective of the
global picture, partly because transnational companies are atypically
large, with many having incomes greater than the gross national
products of developing countries2,3 (see paper in this series by
Henry and Lexchin, to be published in The Lancet on Nov 16). Also,
they represent only a few drug companies worldwide--of over 3000
companies affiliated with the European Federation of Pharmaceutical
Industries and Associations,4 fewer than 100 are likely to be
transnationals (Adrian Towse, personal communication). Moreover, only
one in three countries has an effective legislative framework for the
control of pharmaceutical promotion.5
A review of this nature has other limitations. For instance, little
detailed material is published about the informational aspects of the
industry, and what is available is rarely seen in the standard
medical or scientific press. Instead, insights generally come from
legal, governmental, or industrial reports, the lay media, or
comments in scientific reviews, such sources that are difficult, if
not impossible, to validate. Although recognising these caveats, here
we review how the global industry generates and uses information to
develop medicines, to convince regulators to allow its products to be
marketed, to provide patients and healthcare professionals with
impartial advice, and to promote sale of its products.
Information to steer the search for new products
Transnational companies plan their research programmes for new drugs
in accordance with predictions on future markets and the potential
for creation of lucrative products. Such programmes, which industry
presently estimates cost an average of around US$800 million for each
drug6 (see paper in this series by Henry and Lexchin, to be published
in The Lancet on Nov 16), typically take around 10-12 years to
complete. Planning of the programmes relies crucially on having data
about present pharmacological, pharmaceutical, molecular biological,
technological, and therapeutic advances, global economic and
epidemiological developments, and if possible, knowledge of
competitor activity. All this background material has to be collated
and the programme integrated into the company's particular area of
expertise and its present (and projected) product portfolio. Most of
these steering data remain confidential, a position defended in the
European Union (EU), for example, by the courts.7
The programme proper comprises two phases, which together absorb most
of a new drug's total development costs, leaving a relatively small
proportion (less than 25%; Adrian Towse, personal communication) to
cover the cost of production of the medicines themselves. The initial
discovery phase involves investigative research in vitro and in
animals. Again, very little of the information generated in this
phase is made public, the main exceptions being material included in
patent applications or disclosed during legal disputes. Moreover, to
link any information that does reach the public domain with specific
medicines could be difficult, not least because the product might be
referred to by a code number rather than its subsequent brand or
generic name (for example, propranolol, one of the original
beta-blockers, was referred to in early publications as ICI 45,520).8
The discovery phase is followed by the development phase, in which
research is undertaken in human beings, mainly in clinical trials.
Most of the data generated during this phase again remain
confidential, although some are included in published clinical
reports.
Whatever the research programme, it must be sufficiently durable and
flexible to respond to new challenges and insights; for example,
sildenafil (Viagra) was noted to ameliorate erectile dysfunction only
late in its research programme. After a product's launch into the
marketplace, research continues but along different lines, for
instance the company assesses how its product compares with other,
new technologies and looks for new ways (indications) in which the
product might be used in the future.
Information required by regulators
Regulatory authorities in industrialised countries set out in detail
the information--and so the type and content of research--they
require in the application for a product to be manufactured, sold,
supplied, or promoted. Such requirements have in the past varied from
country to country. Now, however, standardised positions have been
agreed throughout the EU, and between the USA, the EU, and Japan, by
development of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (http://www.ich.org; see paper in this series by Abraham, to be
published in The Lancet on Nov 9). In brief, authorities need
detailed information on: the proposed use for the drug; in what dose
and form it will be available; its quality (eg, consistency, dose,
impurities, stability, contaminants, colourants, additives); details
of its manufacture; its claimed therapeutic actions; and how it is
handled by the body (eg, its absorption, metabolism, distribution,
and excretion). Also needed are results of a battery of safety and
toxicity tests which are designed, for example, to check for damage
to organs, unwanted symptoms, development of cancers, damage to eggs
or sperm, and the likelihood of damage to the fetus.
Although early work in vitro or in animals is mainly done in house or
by contract research organisations (CROs), most research in human
beings is commissioned out and done by independent clinicians and
scientists working with patients or healthy volunteers in clinical
trials. Whatever the form of the research, the company developing the
product has a dominant role, because it (or a CRO working on its
behalf) funds the study, designs the protocol, chooses the
investigators, and in many instances (especially with multicentre
trials), is involved in the collation, interpretation, and reporting
of data. Throughout the research, companies are looking for any
therapeutic features that can be used later as unique selling points
for their products. Because the eventual promotional activity is so
crucial, the company's marketing division may have a role in study
protocol design.
It is the responsibility of the manufacturer (or its agent) to submit
the licence application and supply the necessary supporting data. It
must also propose what the medicine should be used for in practice
(its indications) and draft the contents of impartial product
information about it. Finally, the manufacturer suggests how the
medicine should be made available--ie, whether it should be supplied
prescription-only or sold over the counter. Ultimately, an
application to market the product will be rejected if the authority
judges that the supporting information is inadequate, untrue, or
misleading. As a result of these requirements, vast amounts of data
are submitted to each regulatory authority.
A new-medicine application to the UK authorities, for instance, will
be presented in a dossier of about 250, 1-1�5 kg, A4-sized files,
with the UK Medicines Control Agency's largest submission covering in
total around 100 000 pages. Indeed, so much information is
accumulated by transnational companies (the data submitted are only a
portion of that generated) that their scientists are often unaware
of, or cannot trace, earlier work on file, and as a result find
themselves duplicating research (Rick Fuller, personal communication).
Assessment of the validity of information submitted
Assessing the basis for licensing decisions is difficult, not least
because the full marketing submission is only seen by the applicant
and the relevant regulatory authority or those working on behalf of
the authority. Only a limited amount of data are made public--eg, in
published reports of clinical trials, as a product's summary of
characteristics or Patients' Information Leaflet, as the European
Public Assessment Report for medicines licensed centrally by the EU,
and as various expert US Food and Drugs Administration (FDA) reports.
Also, the work of regulatory authorities is rarely amenable to
scrutiny by independent experts, or their decision-making processes
subject to independent (and public) audit (see paper in this series
by Abraham, to be published in The Lancet on Nov 9). Although some
information is available in the USA, it is not usually clear, for
instance, how complete the submitted data are, or to what extent
regulatory authorities refer to, or can use, data other than those
submitted in the application. Each regulatory authority decides alone
on the adequacy and reliability of the information, whether marketing
of the product is compatible with public-health interests, and, if
so, whether and how the product should be made available.
Some insights into quality of information submitted to regulators are
available from internal reviews or from material published in
journals, with around 30% of submitted clinical trial data published
at the time of licensing, and 50% within 5 years (Bjorn Beerman,
personal communication). For example, a review of the UK Medicines
Control Agency has questioned the adequacy of checks made on the
validity of information received from companies,9 and in the
experience of the UK Drug and Therapeutics Bulletin, few clinical
trials of new medicines are without important shortcomings,
especially with respect to trial design and data interpretation (see
below).
Information published in the medical press
Drug companies recognise the enormous value of publishing clinical
trial reports about their products in medical journals, especially
when the journal is prestigious.10 Such publications are important
because they raise awareness of products. However, to improve sales,
it is also crucial that the published report shows the company's
product in a favourable light. Publication is especially helpful if
the article is published around the time of the product's launch.
Echoing these aspirations, trials with negative results tend to be
published much later than those with more positive conclusions.11
Moreover, the conclusions of trials sponsored by drug companies,
rather than by other sources, tend to be more favourable to the
sponsor's product.12-14
No clear explanation is available for the preponderance of positive
company-sponsored studies. Possibilities include inherent biases in
trial design,15 for instance, by use of inappropriate comparator
drugs,15,16 drug doses,16,17 or methods to assess outcomes.18,19
Occasionally, in attempts to ensure a positive bias, companies have
threatened legal action to stop nominally independent researchers
from publishing negative material.20-23 Moreover, researchers who
communicate negative results have faced intimidation, efforts to
discredit them professionally, and threats of legal action to recover
the value of lost sales.24 Often, the potential for such company
intervention is written into the researcher's contract. For example,
in a sample of US research centres, around 30% of contracts with
researchers allowed the sponsoring company to delete information from
the report and to delay publication.22 Also, participation in an
academic-industry relationship and commercialisation of university
research are both associated with delays in publication.25
One initiative to address such sources of bias has been introduced by
journals that are members of the International Committee of Medical
Journal Editors, including the BMJ and The Lancet. These journals now
require contributors to disclose details of their own and their
funders' roles in studies.26,27 Such contributors have to declare
that they accept full responsibility for how the study was conducted,
had access to the data, and controlled the decision to publish.
The predominance of positive results in published reports might also
be associated with the income journals receive from drug-company
advertising. As a result, some editors might find it difficult not to
comply with industry's wishes to publish material, no matter how poor
the study might be, or to change the negative wording of trial
reports submitted by independent researchers. Whatever their origin,
trials with positive results are more likely than others to be:
selected for presentation at scientific meetings; reported in print;
published promptly; published as full reports; published in
widely-read journals; published in English; published in more than
one report; and cited in related reports.28
Generation of information and wider research implications
The pharmaceutical industry is the single largest sponsor of medical
research--and thus the largest generator of related information--in,
for example, Canada,29 the USA,30 and the UK,31 and in some countries
it is the only realistic source of such support. Industry-funded
research is overwhelmingly drug-oriented, so it could distort a
country's research effort by, for instance, diverting resources and
personnel away from non-drug interventions or other aspects of health
care. Moreover, as increasing numbers of medical researchers are
drawn to the industry, alternative voices and opinions can become
muted, and novel avenues of research might be overlooked.
Is is widely accepted that 90% of the world's health problems (mainly
those of developing countries) attract only 10% of global health
resources (the so-called 10/90 health-research gap),32,33 and
industry's investment pattern might contribute to this discrepancy.
Transnational companies have traditionally ignored work on treatments
for diseases that occur mainly in developing countries, because they
know even if appropriate treatments were produced, they would not
bring adequate returns.34 A second potential distorting factor
resulting from patterns of research is so-called evidence capture,
whereby health-care policies blindly follow published evidence
irrespective of whether the information provided is reliable or
appropriate to the needs of society at large. Industry's research
interests and activity dominate research outputs so much--eg, trials
on the value of antiarthritic drugs far outnumber those on walking
sticks--that the sheer weight of new evidence, rather than its
quality, might lead to inappropriate shifts in therapeutic practice
away from tried, familiar, and usually cheaper approaches, to novel,
unfamiliar, and generally more expensive alternatives that offer no
real clinical advantage.
Impartial information provided by companies to users
In many industrialised countries, it is standard for drug companies
to provide impartial information about their products to health-care
professionals and patients (see section on information required by
regulators). Such information includes summaries of product
characteristics, packaging and labelling details, and Patients'
Information Leaflets. This material, which is drafted, published,
paid for, and distributed by the company, is usually required by law,
has legal status, and is mainly controlled by regulatory authorities.
In some countries, the summary of product characteristics might be
the only impartial information available to those prescribing or
taking medicines, and so it is of great value. However, information
provided in this way still has inevitable limitations, since it can
only refer in detail to the accompanying product and so cannot advise
on its value compared with other medicines or non-drug treatments.
Moreover, summaries of product characteristics can fail in their
primary public-health objective to inform clinicians and patients, by
offering advice that is unclear or impractical.35 Part of the
responsibility for such failure lies with the regulatory authority
itself.
Promotional information
By announcing a medicine's availability and its potential use,
advertising can be valuable to prescribers and patients. It is also
an important component of drug-company business, with, for instance,
much more money spent on promotion than on research and
development,36 or on provision of impartial information. In the UK
(one of the few places where advertising spend is capped), adherence
to the Pharmaceutical Price Regulation Scheme (PPRS) means that for
every pound spent by the industry on impartial information, around
five pounds will be spent on promotional activity.
Work on promotion starts at the trial-design stage, when the company
plans how to obtain information that might point to unique selling
points for the new product. Once these therapeutic advantages have
been defined and the company feels the product will obtain marketing
authorisation, the campaign proper begins. In transnational
companies, such campaigns will be carefully orchestrated so that
messages remain consistent when presented to different audiences over
time, and from country to country--eg, in media outlets and printed
promotion, as relayed by drug-company representatives or during
organised symposia.
The main stages in any promotional campaign for a new product
concentrate on dissemination of information rather than its
generation. Usually, the first step is to increase the target
audience's awareness of a disorder and to highlight present deficits
in its treatment. For example, one announcement coupled the
observation that "psychologists estimate that one in 15 people suffer
from acute social awkwardness" with the fact that "a new drug that
relieves shyness could be available within a year".37 Having
persuaded people of the treatment need, the next stage is to
introduce the new medicine, telling of its unique advantages. The
ultimate aim is to induce clinicians to prescribe the product and for
familiarised members of the public to ask for it. Ultimately, a
successful campaign will develop, secure, and reinforce brand
loyalty, objectives similar to promotional campaigns for longer
established products.
Traditional channels for promotion of prescription-only products
includes advertisements, mailings, and visits to clinicians by
drug-company representatives--New Zealand and the USA also allow
promotion direct to the public. Furthermore, the company's marketing
department--working with outside agents such as public-relations
companies and medical education agencies--will try to ensure that
supportive articles--ideally editorials--are placed in relevant
specialist journals; products are endorsed by opinion-leaders and
journalists;38,39 product-labelled gifts (eg, pens, notepads,
calendars) are displayed by health-care professionals and distributed
at events (eg, symposia, postgraduate educational meetings); the lay
press publishes disguised promotional material;40 and products are
championed by consumer (patients') support groups.
These overtly promotional methods are bolstered by more indirect
leverage. For example, drug company-sponsored science-teaching
programmes in schools (now commonplace in the UK) can induce loyalty
to industry at an early age and encourage the idea that medicines are
necessarily good solutions to ill health. Funding of prizes,
scholarships, or travel bursaries to students, scientists, and
clinicians also inevitably engenders company loyalty.
Regulatory authorities are ultimately responsible for ensuring that
promotional activity is at least accurate, truthful, balanced,
up-to-date, unlikely to mislead,41 and consistent with the summary of
product characteristics or its equivalent. However, in many
countries, regulatory authorities are either absent or ineffective,
and in industrialised countries, they typically devolve much of the
policing to the industry itself. Perhaps, as a result, inappropriate
promotion is commonplace. However strict and well-policed the
controls in individual countries, cross-border promotion offers a
particular challenge. Regulators can find it difficult to deal with
promotional material from another country, where the relevant
legislation is different to that in their country or where
promotional claims have no traceable or verifiable source, as can
arise with advertising on the internet.
When promotional information distorts
There is no doubt that medicines offer enormous health benefits;
however, a crucial issue for patients and society at large is that
treatment choices are made rationally, with patients receiving the
best available medicines given in such a way that fullest advantage
is ensured. These goals are unlikely to be met if the reasons for
prescription are distorted, and end up tipping the balance away from
patients' interests and towards those of the pharmaceutical industry.
The more effective the advertising and any accompanying promotional
devices, the greater the potential for such distortion. Rational
prescribing is inevitably threatened when, for example,
opinion-leaders are briefed, promoted, cultured, and supported by
manufacturers;39 when patients' advocacy groups are funded and
supported by the industry (eg, in the UK, Pfizer, manufacturer of
sildenafil, supports the Impotence Association
[http://www.impotence.org.uk] and the Men's Health Forum [http://www.
menshealthforum.org.uk]); when, as in many countries, there are few,
independent, non-commercial sources of information, leaving
prescribers heavily reliant on drug-company representatives for their
information;5 when controls of promotion are weak and promotional
excesses greatest;4 when claims in drug advertising are not supported
by the accompanying bibliographical references;42 or when most young
doctors have gifts endorsing particular companies or their products.43
Although any company could, in theory, exert influence by these
means, the transnational companies have the resources to do so in an
organised manner, and it is they who tend to set the norms. Moreover,
these companies can develop and promote their products worldwide,
with campaigns to recruit and influence opinion-leaders and
journalists.40 Finally, large companies often have enough influence
to give them direct access to government policy-making. For instance,
it is difficult to see how a government could resist pressure from
companies with revenues that exceed their country's gross national
product. Presently in the UK, representatives of the pharmaceutical
industry and ministers from five governmental departments meet
regularly as part of a Pharmaceutical Industry Competitiveness Task
Force, to develop policies designed to strengthen the competitiveness
of the UK business environment for the innovative pharmaceutical
industry.44
Conclusions
The pharmaceutical industry--and in particular large transnational
companies--generates and collates vast amounts of information. Much
of this material remains secret or is shared exclusively with
regulatory authorities. A small proportion is publicly available,
mainly as published clinical trials, promotional material, and
impartial treatment advice directed to prescribers and patients.
Through their investment in research, transnational companies have an
important effect on the direction of medical research generally; via
their promotional and educational activity, they are probably the
biggest individual influence on prescribing practice. For the
pharmaceutical industry, investment in information is time and money
well spent. However, the huge scale of work involved, lack of
openness, accompanying duplication, and distortion of the overall
research effort and resulting messages make the business of
information-generation inefficient and threatens patients' interests.
Conflict of interest statement
Joe Collier and Ike Iheanacho are Editor and Deputy Editor,
respectively, of Drug and Therapeutics Bulletin.
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