E-DRUG: Priority Medicines for Europe and the World (2)
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Position statement by the Medicines in Europe Forum on the Dutch
EU Presidency initiative entitled
"Priority Medicines for the Citizens of Europe"
The Hague, 18 November 2004
MEDICINES IN EUROPE FORUM
Summary
The initiative by the Dutch Presidency of the European Union is welcomed by
the Medicines in Europe Forum, given the enormous gap between the drug
market and public health requirements in Europe and the rest of the world,
especially poor countries.
The Medicines in Europe Forum points out, however, that development of new
drugs is not the chief priority among possible measures designed to
tangibly improve the health of European citizens. The leading priorities
are the following:
-large-scale primary prevention, notably based on nutritional and
environmental measures, as recommended by the World Health Organization at
the 57th World Health Assembly in 2004;
-better prevention of errors linked to the use of existing drugs, notably
through better packaging;
-better prevention of adverse effects of existing drugs, through more
effective and transparent pharmacovigilance.
Regarding new drug development, the Medicines in Europe Forum identifies
the following priorities:
- relevant comparative pre-marketing evaluation, in order to avoid the
release of drugs with unknown added therapeutic value, which may prove to
be more harmful than existing products;
-research aimed at palliating for current inadequacies in the following
areas: useful older drugs that are considered no longer profitable by drug
companies; drug utilization by patients; comparisons with non drug
treatments; drugs for health disorders whose severity sometimes serves as a
pretext for inadequate pre-marketing assessment (cancer, multiple
sclerosis, Alzheimer's disease, viral infections, some rheumatic diseases
and related pain); drugs for groups of patients at special risk,
particularly the elderly ;
-decisions on research priorities and funding must be made transparently
vis-`-vis European citizens.
Increasingly numerous pharmacovigilance scandals are shaking the
foundations of the drug market and revealing the failings of drug companies
and medicines agencies; decisive action by Member States and national
health authorities is urgently needed.
The Medicines in Europe Forum would particularly welcome an initiative by
the EU Presidency aimed at tightening rules on drug evaluation, focusing
research on the most needy patients (including patients outside the EU),
and making primary prevention a leading priority.
The Medicines in Europe Forum, a group associating 60 organisations of
patients, consumers, health professionals and health insurers in 12
European Union Member States, welcomes the initiative taken by the Dutch
Presidency of the European Union in the field of medicinal products. All
member states are now confronted with a growing financial crisis as they
struggle to provide their citizens with access to increasingly expensive
new drugs, whose added therapeutic value relative to existing preventive or
curative treatments is rarely known. A re-assessment of research priorities
can only be beneficial, and the Dutch Presidency should be praised for
launching a public debate.
The Medicines in Europe Forum nevertheless considers that, in its present
form, the "Priority Medicines" initiative will only contribute to improving
the health of EU citizens if it takes into account other key determinants.
The reforms most urgently needed in Europe concern primary prevention,
based on non drug measures, and better use of existing drugs in order to
avoid medication errors and adverse effects.
The development of new "priority" drugs is important, but with two provisos
: new drugs must be rigorously evaluated prior to their market release; and
research priorities must correspond to concrete needs identified by
epidemiological studies. These needs concern a number of patient groups in
Europe, and far larger population groups in poor countries, that Europe
must undertake to assist.
Making primary prevention a true priority
Many of the health problems affecting European citizens require first and
foremost preventing measures. Large-scale primary preventive measures
targeting nutrition, the environment, infections, accidents and behaviors
are therefore crucial. Funds devoted to these measures would have a bigger
impact on public health than would the same funds used for curative
treatment. This is the notion underlying the WHO Global Strategy on Diet,
Physical Activity and Health defined at the 57th World Health Assembly in
2004.
For example, obesity, cardiovascular diseases and diabetes are mainly
linked to dietary and lifestyle habits. What is needed is not yet another
new cholesterol lowering or antidiabetic drug, but better education of
children and health professionals, and measures to resist the lobbying of
the food industry.
The fight against smoking, which is a leading cause of cardiovascular
diseases and cancer, is currently far too inadequate. Here again, what we
need most is not new smoking withdrawal drugs but large-scale public health
campaigns and more effective constraints on the tobacco industry.
The toxicity of new chemical substances used in agriculture and industry is
barely assessed prior to marketing, and even less so once the product is in
use. The number of new chemicals continues to rise, and studies of their
impact on the environment, animals and humans are inadequate. We encourage
the Dutch Presidency of the EU to take the measures necessary to ensure
that the risks associated with new chemical substances, and especially the
risk of cancer, are properly assessed.
Preventing errors linked to the use of medicines:
don9t forget drugs already on the market
The European Union has consistently failed to take the measures necessary
to prevent medication errors, the high human and financial costs of which
have been documented in the United States and in some European Union Member
States. These errors are partly due to failures in professional practices,
but also to inadequate packaging and poor quality information for patients
(labeling, patient information leaflet, etc.). For example, ambiguous
expression of a drug concentration or poor design of a dosing device can
lead to the administration of a toxic dose, or an inadequate warning on the
labeling of a teratogenic drug can lead to its use by a pregnant woman.
In addition to the need for a stronger and more transparent adverse drug
reactions monitoring (pharmacovigilance), we also need a program for
reporting medication errors, analyzing the causes, and proposing strong
measures to prevent them. When Directive 2004/27/EC is transposed into
national law, it should lead to slight improvements in some packaging items
for new drugs such as more legible international non proprietary name
(including in Braille), and user-tested patient information leaflets. But
many medication errors will continue to occur if nothing is done to improve
the packaging of existing drugs.
The Medicines in Europe Forum welcomes the Council of Europe's initiative
aimed at preventing medication errors. We note that the European Commission
and the European Medicines Agency also express the wish to improve patient
information on medicines, but currently pay little attention to the
information provided by companies on their product packaging and patient
leaflets, and fail to ensure that all unit doses permanently bear
identifiers.
The Medicines in Europe Forum would also welcome an initiative by the
Presidency that targets drugs that are already on the market.
Preventing adverse effects of existing drugs
The European Union has long had a regulatory framework on
pharmacovigilance, and each Member State has its national pharmacovigilance
system. In practice, however, the monitoring and prevention of adverse
effects are both highly inadequate: scant attention is paid to adverse
effects in pre-marketing clinical trials (trials tend to focus on efficacy,
not on risk); the adverse effects reporting system is inadequate (little
involvement of health professionals and patients); the processes of data
collection and analysis are unacceptably secretive; and little reliable
information trickles down to health care professionals or patients.
One major priority is to reinforce pharmacovigilance through a transparent
information policy for health professionals and patients, which is a
crucial first step in their effective participation in adverse effect
prevention.
Member State medicines agencies and health authorities must start to oblige
companies to complete the pharmacovigilance studies on which marketing
authorisation is often conditional. Too often these demands are simply
ignored, and any results are rarely made public. Medicines agencies must
also reassess the risk-benefit balance at the time of the five-yearly
renewal of marketing authorization, notably by examining whether safer
drugs have arrived on the market in the meantime.
The Medicines in Europe Forum would also welcome an initiative by the
Presidency in favor of more active and more transparent pharmacovigilance.
Making thorough, reliable assessment of new drugs a priority
After an improvement in drug evaluation in the early 1980s, following
application of the first European directive on marketing authorization and
on pharmacovigilance, the regulatory process has gradually fallen into
disarray. Pharmaceutical majors drew medicines agencies (including the
European Medicines Agency) into an international compromise on drug
assessment (the International Conference on Harmonisation or ICH process),
which permits new drugs to be marketed on the basis of a not too exacting
evaluation dossier. As a result, most new drugs are authorized without
proper knowledge of their added therapeutic value or their optimal
conditions of use.
The priority for drug development in Europe is to stop authorizing
inadequately assessed drugs in the name of free trade, and to re-evaluate
drugs that are already on the market, in order to improve the rational use
of existing treatments.
The Medicines in Europe Forum proposes the following measures:
- when a new drug has not been compared with a reference treatment
available for the same disease or the same symptom, medicines agencies must
demand a relevant comparative assessment before granting marketing
authorization. More and more new drugs offer patients no tangible
advantages, while exposing them to greater risks; some drugs have to be
withdrawn after years on the market at exorbitant prices. It is
irresponsible to authorize drugs with poorly documented benefits and risks
simply in the name of free trade.
- when comparative trials of a new drug are flawed (inadequate or excessive
dose of the reference treatment, inappropriate trial populations, etc.),
medicines agencies must demand new comparisons at optimal doses in patients
for whom the product is actually intended. Irrelevant trials are a waste of
resources, and it is the taxpayer who eventually foots the bill.
- companies must be obliged to determine how long their drugs take to be
effective, and when efficacy starts to wane. Likewise, the optimal
treatment duration must be properly determined in order to avoid
unnecessary drug expenditure and adverse effects.
- regarding the optimal dose regimen, dose-finding studies are often the
weakest element of clinical evaluation dossiers on new drugs (or old drugs
proposed for new indications), meaning that the therapeutic margin between
effective doses and doses inducing adverse effects is poorly defined.
- identification of adverse effects is not a sufficient priority in
clinical trials: the main focus for companies and their investigators is
simply to show that a product is effective. Safety information is therefore
lacking.
- drugs are often authorized for second-line use because they are not more
effective than existing options in first-line treatment. Such
authorizations should only be granted if the new drug has a different
adverse effects profile from that of the reference drug, or if it is
effective when the reference drug fails. These questions must be addressed
in pre-marketing trials. The same applies to drugs authorized for third- or
fourth-line used, in cancer therapy for example.
- data are often lacking on patients at special risk, not only patients
with renal or hepatic failure, but also elderly patients, in whom the risk
of drug-related complications is particularly high.
Currently, most clinical and pre-clinical studies in Europe are funded by
pharmaceutical companies, who have a fairly free hand. Many drugs are
authorized (even though they are inadequately evaluated) on condition that
the company conducts further trials, but this obligation is often ignored.
Before clinical trials begin, drug development projects should be examined
by medicines agencies, or by independent bodies if agencies, being
financially dependent on drug companies, fail to deliver, in order to
determine:
- the adverse effects that are most likely to occur in clinical trials,
based on prior animal experiments, and that should be particularly looked
at ;
- what treatments already exist in the therapeutic indication at hand; what
patients and health professionals really want; and the types of comparative
trials required.
Research priorities targeting current inadequacies
The Dutch Presidency's initiative aimed at redefining research priorities
is welcome because it highlights discrepancies between drug development and
patients' real needs: most drugs are currently developed for a small number
of "profitable" health diseases, to the detriment of other important but
not profitable diseases, according to industry.
In recent years the European Union has developed certain measures intended
to meet the needs of patients with rare diseases, one example being
Regulation 141/2000/EC on orphan drugs. The Medicines in Europe Forum
wishes to see this regulation properly implemented: in particular, orphan
drug status must be attributed (and maintained along the years) only to
products intended for very small patient groups, and progress in the
treatment of these diseases should be regularly evaluated.
The European Union is currently drawing up a Regulation on pediatric drugs.
Some groups of children need specific formulations and dose strengths, and
certain drugs need to be evaluated in specific child populations. This
useful project should not delude us into believing that so far medicines
for children were totally lacking: for some conditions there are actually
many of them and they are often excessively consumed (e.g. antibiotics in
some countries, psychotropics in others). The Medicines in Europe Forum
recommends that populations of children lacking appropriate drugs be
precisely identified, and not defined simply on the basis of current
practices, which are often irrational, sometimes irrelevant, and
occasionally dangerous.
In many other areas the problem is not a lack of drugs per se, but rather
inadequate assessment of existing options: how best to use them, how to
avoid their adverse effects, and especially how to choose the best
treatment. In the view of the Medicines in Europe Forum, research
priorities should aim to fill gaps in our current knowledge. For example:
- useful old drugs, which are generally cheap, are no longer studied in
comparative trials (dose-finding studies, comparative class trials, etc.).
Worse, companies sometimes withdraw these products from the market simply
because they are no longer profitable. Support for research on these drugs,
and perhaps assistance with their marketing, should be treated as a
priority in particular cases. One outstanding example is that of diuretics
used as antihypertensive drugs ;
- few reliable data, and especially observational studies, are available on
the optimal conditions of drug use, especially during long-term treatments
and for drugs used in multiple combinations. Such studies could improve the
use of existing drugs, limiting both medication errors and adverse effects
;
- too few comparisons between drug and non drug treatments are available,
owing to the separation between research teams and divergent financial
interests. Yet non-drug treatments (surgery, physiotherapy, behavior
psychotherapy, etc.) are potentially beneficial in many areas ;
- in the field of cancer therapy, many drug combinations are used without
having been properly evaluated. Even in recommended treatment protocols,
dose regimens differ from one side of the Atlantic to the other, or from
one "school" to another. As cytotoxic drugs often have major adverse
effects, the different protocols used for a given indication should be
identified and evaluated.
- in serious illnesses such as multiple sclerosis and Alzheimer's disease,
drugs should only be authorized when they have been compared with the
reference treatment, especially when placebo-controlled trials show only a
marginal benefit and serious adverse effects. The severity of a given
disease and the limited efficacy of a reference treatment in no way justify
taking short-cuts in the pre-marketing evaluation: on the contrary, strict
assessment is needed to offer patients a realistic hope of relief ;
- regarding pain relief, new drugs are often tested in conditions for which
they are not actually intended; this is particularly the case of WHO step
II analgesics.
- in rheumatoid arthritis and other rheumatic diseases, almost all newly
marketed drugs are immunosuppressants. The long-term risks of such
treatments call for research on alternative approaches.
- in viral diseases such as hepatitis, treatment efficacy is based on viral
load. This is an acceptable provisional endpoint, for want of anything
better, but what really matters is the impact of treatment on mortality and
morbidity.
Restoring confidence and credibility of authorities through transparency
Patients, health care professionals and citizens of the European Union are
ready to support effective health initiatives. But experience shows that
most research in Europe, and especially drug development, is done by
private companies, and that regulatory agencies are not sufficiently
demanding. As a result, companies have a free hand in their search for
short-term profitability, regardless of patients' interests. This situation
has generated a plethora of drugs that offer no therapeutic advance
whatsoever, and many of which target a limited number of profitable health
problems.
If public funds are to be invested, the choice of research priorities, and
the monitoring of this research, must be fully independent. Transparency is
the best way of guaranteeing this independence. The Medicines in Europe
Forum proposes the following measures:
- once priorities have been identified, a schedule of research work to be
funded by the European Union should be made public;
- continued public funding should be conditional on due respect of the
research schedule;
- public funding should be conditional on transparent research costs;
- health professionals and patients should be involved in defining research
priorities, and also in controlling public funding;
- a public register of clinical research priorities receiving partial or
total public funding must be created.
- when a new drug hits the market the results of all clinical research
should be made public, including trials with negative results, prematurely
terminated trials, and any protocol modifications.
Supporting drug development for neglected diseases in poor countries
During the co-decision procedure preceding the adoption of Directive
2004/27/EC on medicinal products, the Medicines in Europe Forum noted a
regrettable lack of interest on the part of the
European Commission, health ministers, and some European Members of
Parliament in access to drugs for the poorest countries.
The Medicines in Europe Forum welcomes the fact that the WHO report on drug
priorities commissioned by the Dutch Presidency mentions the needs of poor
countries. The Forum hopes that this will translate into a decisive
financial and intellectual commitment by the European Union to research
into the most serious diseases affecting these countries (malaria,
tuberculosis, HIV/AIDS, sleeping sickness, etc.), and the adaptation of
existing drugs to use in tropical countries.
The annex on neglected diseases in the WHO report entitled "Priority Drugs
for Europe and the World" commissioned by the Dutch Presidency of the
European Union describes the scale of the problem and suggests a number of
steps designed to start to rectify it.
The Medicines in Europe Forum
http://www.prescrire.org/aLaUne/dossierEuropeCollectif.php
November 2004