Memorandum by Professor Andrew Herxheimer
(P165)
PERSONAL STATEMENT
I have taught clinical pharmacology and therapeutics
at London University from 1960 to 1991, most recently at Charing
Cross and Westminster Medical School. I founded Drug and Therapeutics
Bulletin, published by Consumers' Association, in 1962 and
edited it until 1992. I chaired the International Society of Drug
Bulletins from its foundation in 1986 till 1996, and the Health
Working Group of Consumers International. I have many times been
a consultant to the World Health Organization. I am interested
in all aspects of providing independent, unbiased, clear and concise
information about therapeutic interventions to professionals and
the public, and have long experience of observing the pharmaceutical
industry at work.
Since 1992 I have worked in the Cochrane Collaboration
and am now Emeritus Fellow of the UK Cochrane Centre in Oxford.
If the Committee wishes, I would be willing
to give oral evidence.
THIS MEMORANDUM
FOCUSES ON
THE FOLLOWING
MAIN ISSUES,
THE FIRST
THREE OF
WHICH CONTRIBUTE
SUBSTANTIALLY TO
A SYSTEMATIC
OVER-ESTIMATION
OF DRUG
BENEFIT AND
UNDERESTIMATION OF
HARM
1. The influence of the industry on medical
practice and on the regulation of medicines is pervasive, overwhelming
and relentless. The problem of undue and unhelpful influence is,
arguably, related much more to the extent and volume of industry
influence, rather than to outright malpractice.
2. The industry takes little pro-active
interest in adverse effects of drugs; only legal or commercial
concerns move it to do more than the regulators require. The drug
regulatory framework encourages this complacency by relying excessively
on pre-marketing clinical trials in defining drug safety profiles.
3. The nature and extent of drug marketing
is worrying, not least because of the intensity of promotion at
and soon after a drug is launched—ie when relatively little
is known about the performance of a drug in clinical practice.
A conspicuous example of the negative impact of drug marketing
relates to recommended drug dosage, which is often inappropriately
uniform. It is not true that one size fits all, as marketing often
demands; industry and the regulators need to take much more account
of important differences among users.
4. What might be the most effective ways
of containing undue industry influence in the future?
1. THE INDUSTRY'S
INFLUENCE
The development of drug regulation in the UK
that followed the thalidomide disaster has been described in detail
by John Abraham (1995). From the beginning in 1962, when Lord
Cohen's Committee reported on the testing and regulation of new
drugs, the industry has greatly influenced what was to be done.
Close collaboration between industry, ministers and civil servants
on the principles and details of regulatory policies has continued,
albeit with a marked shift towards international regulation since
the 1990s.[15]
During all this time the Ministry of Health and its successors,
the DHSS and the DoH have been the sponsoring Department for the
pharmaceutical industry, responsible for its welfare—while
also of course being its biggest customer. The industry's exports
were then and still remain important to the national economy,
and might be threatened by strict regulation.
Government and industry have strived for and
largely achieved a family atmosphere of cooperation and trust—hardly
dimmed by some adversarial episodes—and reinforced by the
blanket secrecy guaranteed by s 118 of the Medicines Act, 1968.
Over the years many personal relationships have grown between
regulatory officials and the staff of pharmaceutical companies,
helped by a "revolving door" and frequent meetings to
address regulatory matters. The argument has been that experience
of working in the industry is highly desirable, if not essential,
to understanding the practical implications of regulatory issues.
Similarly comfortable contacts have existed between many of the
members of the Committee on Safety of Medicines and industry,
and this continues.
These close working relationships over decades
have meant that industry views have been much more prominently
represented—and to a notable extent internalised—in
drug regulation than the interests of patients and consumers,
or of clinicians.
The influence of the industry on medical practice
is enormous, but largely intangible and unseen. It is mediated
by its internationally and nationally dominant position in determining
the agendas of therapeutic research and providing funding for
it, by the huge volume of pharmaceutical promotion, direct and
indirect (including its scientific publication policies and its
selective support of continuing medical education), and intense
public relations activity. Competition in the industry is based
far more on innovative marketing methods and public relations
than on the effectiveness and safety of its products.
The industry tries its considerable best to
control information about its products and its work. It naturally
wishes to guard all unfavourable information, claiming commercial
and proprietorial rights, and ceaselessly pushes the positive
aspects at all its target constituencies—prescribers, patients,
consumers, health service managers, politicians. This is called
"Providing information".
One seriously harmful result of these frenetic
activities, which governments have ignored, is that drug treatments
are uppermost in the minds of doctors and the public, and non-drug
treatments (including non-intervention) are very often not adequately
considered. There is much less money to promote these.
Recommendations
1.1 The sponsoring Department for the pharmaceutical
industry should be the Department of Trade and Industry instead
of the Department of Health. Similarly, responsibility for regulation
of the pharmaceutical industry in Europe should rest primarily
with the Directorate-General for Health and Consumer Protection,
rather than the Commission's departments for Enterprise and Trade.
1.2 Policies should be developed for reducing
the potential for conflicts of interest in medicines regulation,
including complete transparency about the conflicts that may exist.
1.3 The NHS, which pays for the promotion of
medicines as an important part of their cost, should thoroughly
investigate the health impacts of promotion, including the benefits
and harms of various forms of medicalisation of common problems,
and of disease awareness campaigns aimed at the public. It would
be logical to fund such research through a small levy on promotional
spending by companies.
1.4 If self-regulation of pharmaceutical promotion
by the industry is to continue, independently chosen representatives
of the public interest should play a substantial if not dominant
part in it.
2. ADVERSE EFFECTS
OF DRUGS
All medicines have unwanted effects, which prescribers
and users must understand and be able to manage. They need to
know what may happen and what to do if it does. They have to use
the drug in ways that minimise the chance of unwanted effects
and their intensity.
The task of medicines regulation is to assure
their "safety, quality and efficacy". This work is done
mainly before products are licensed. The regulators have to satisfy
themselves about these before approving a product, and for this
purpose require detailed data from the company, including "safety
data" from studies of pharmacology and toxicology in animals,
studies in healthy volunteers and in patients. These studies are
primarily intended to demonstrate the harmlessness ("safety")
of the drug. Companies themselves undertake and commission the
large amount of work needed to meet all the regulators' requirements.
They do not usually investigate how various adverse effects are
produced.
After a licence has been issued and the product
marketed the Post-Licensing Division of the MHRA is in charge
of continuing surveillance of safety; companies must report to
the MHRA all adverse events they become aware of. This is the
mainstay of what is called pharmacovigilance, but the scope of
pharmacovigilance is, in practice, quite limited. Lack of transparency
has proved an obstacle to assessing its quality and impact overall,
though there are obvious grounds for concern (Medawar & Herxheimer,
2003). Companies rarely do more research on safety aspects unless
they need to defend the product when a serious adverse effect
is alleged or suspected, or to show that it is safer than a competing
product. The design of studies performed in these circumstances
is liable to be much influenced by legal and commercial considerations.
It is unusual for regulators to require (as
opposed to request) companies to do further studies of adverse
effects on a licensed product; they may not have the power to
do so, nor can they check that such studies are adequately designed
and performed. It is no-one's job to undertake or to fund such
work. What little work is done tends to be done by interested
independent researchers without specific funding.
Since the Inquiry focuses on the impact of the
industry on the regulatory review of drug safety and efficacy,
it may be necessary to discuss some aspects of pharmacovigilance
in detail, and I have therefore tried to put these briefly into
context in Appendix A.
Recommendations
2.1 Research on the natural history, mechanisms,
prevention and clinical management of adverse drug reactions (ADRs)
should be encouraged and publicly funded. It should be independent
of industry and of drug regulatory agencies. Consideration might
be given to organising the funding of such work through a modest
levy on pharmaceutical sales.
2.2 Adverse drug reactions represent only
one (the most visible) aspect of the ill-effects of drugs on health.
The impact of drug use on communities, including the medicalisation
of personal problems and the drawbacks of "disease awareness"
promotion need also to be addressed.
3. DOSES
The doses to be recommended for new drugs are
decided by the manufacturers, on the basis of their experimental
dose-ranging studies in healthy volunteers and patients. These
studies are submitted as part of the licensing application, but
few are published. Many recommended drug doses are higher than
is medically necessary, for two reasons (Herxheimer 1991; Cohen
2001).
The first is that manufacturers aim for a dose
that will be effective in the great majority of people given it.
A simple dosage scheme, one-size-fits-all, appeals to prescribers
and so helps market penetration. Complicated dosage regimens tend
to inconvenience doctors and to create practical difficulties
for many patients. Also, doctors and patients will not wish to
use the drug if it is ineffective in a substantial proportion
of people. So drugs are typically introduced at a dose that will
be effective in the highest proportion of the target population.
But patients vary quite widely in their sensitivity to various
drugs, and the standard "recommended" dose is too high
for many, causing unwanted effects that range from transient unpleasantness
and inconvenience to serious harm, while a lower dose would have
been effective and much less likely to cause trouble.
The second reason for doses being higher than
necessary or desirable is that manufacturers prefer doses rounded
up to "convenient" numbers, especially those ending
with the digits 1, 2, 5, and 0. The dose excess due to such digit
preference may be as much as 70% of the correct dose and on average
is probably 25% (Herxheimer 1991).
Drug regulators have traditionally paid little
attention to dose and generally accept the doses proposed when
drugs are first marketed. One reason for this may be that all
the clinical trials that prove the drug's effectiveness have been
performed at those doses: to require new trials at lower doses
would cause long delays and high costs, which would be hard to
justify. About one in six drugs have had dosage recommendations
modified (generally downwards) at some time after licensing.
Recommendations
3.1 Companies should be required to submit
evidence on the lowest effective dose for all drugs for any significant
minority of users, and regulators should require that this dosage
will be in the range of doses to be marketed.
3.2 Companies should be required to submit,
and after licensing to publish, dose-effect data for all the intended
beneficial effects, and the most important unwanted effects of
the drug.
4. What might be the most effective ways
of containing undue industry influence in the future?
Many factors complicate the Health Committee's
task in assessing the impact of the pharmaceutical industry's
influence, and addressing the problems it creates. The major factors
include: the extent of acceptance and complicity among other stakeholders;
the increasingly international character of the pharmaceutical
industry; the introduction of supranational regulatory mechanisms
and standards; and the traditional and pervasive secrecy in this
field, in particular relating to drug risks and harms.
The options available for proposing reform seem
limited, other than in relation to the last of these factors.
Transparency seems all the more critical because of the rapidly
waning influence of national authority in drug control. I believe
there would be overwhelming support from all concerned about the
adverse impacts of industry influence, for recommendations from
the Committee that might lead to greater transparency in this
field. Freedom of information—including freedom of expression
and protection for whistle-blowers—is a prerequisite to
the planning and implementation of reform. Without this it is
unrealistic to suppose that pernicious influence can be contained.
In the absence of transparency, it would seem much more likely
to grow.
References
Abraham J. Science, politics and the pharmaceutical
industry (esp. Chapter 2). London: UCL Press, 1995.
Cohen, Jay. Overdose: the case against the drug
companies. New York: Tarcher/Putnam 2001.
Herxheimer A. How much drug in the tablet? Lancet
1991; 337: 346-8.
Medawar C, Herxheimer A.Risk of suicidality
and dependence with Paroxetine: Comparing Yellow Card reports
of suspected adverse drug reactions with reports from users. Int.
J. Risk & Safety in Medicine 2003; 16: 3-17.
15 This trend was underlined by the founding of the
European single market and the setting up of the European Medicines
Evaluation Agency, and the establishment of the International
Conference on Harmonisation (on technical requirements for registration
of pharmaceuticals for human use). Back
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