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[e-drug] EU Regulation on medicines for paediatric use

E-DRUG: EU Regulation on medicines for paediatric use

Position Statement by the Medicines in Europe Forum 

On the draft regulation prepared by the European Parliament and European
Council on medicines for paediatric use

The Medicines in Europe Forum welcomes the EU initiative aimed at making
appropriate drugs available for children and their caregivers. The Forum
has closely examined the draft regulation on paediatric drugs presented by
the European Commission in autumn 2004.

The draft regulation mentions several measures aimed at encouraging the
funding of paediatric drug development:

- drug substances protected by patents or by supplementary protection
certificates: a "paediatric investigation plan" must be submitted at the
same time as the marketing application (except for drugs that do not
concern children); the data protection is automatically extended if the
plan is implemented, even if authorisation for paediatric use is not

- drug substances that are no longer protected: creation of a specific
marketing authorisation for paediatric use, with major rewards in terms of
the duration of data protection.
However, as usual for a draft proposed by the Enterprise
Directorate-General of the European Commission, the project centres on the
financial concerns of pharmaceutical firms and on technical measures
intended to meet these concerns. It leaves the initiative entirely in the
hands of drug companies and neglects the overriding public health
objective, which is to provide every possible means of treating children
If the draft regulation on paediatric drugs were to be adopted as it
currently stands, it would result in a paediatric medicines market that
fails to meet the needs of those children lacking new treatments, and would
also increase paediatric consumption of useless and risky drugs.
The Medicines in Europe Forum considers that the text must be refocused on
the initial public health objective, which is to improve the health of all
children in the European Union. A thorough inventory of real needs must be
conducted by an independent, publicly funded authority, in order to orient
research efforts most efficiently. Research incentives must be available to
both the public and the private sector. The initiative must not be left
simply to the goodwill of private drug companies. The rules of the game
must be clear, so as to avoid abuse and misappropriation of incentives and
funds. Rewards must be proportional to spending on research and development
of really needed drugs. Pharmacovigilance must be reinforced in the
paediatric clinical trial setting.

The Medicines in Europe Forum has several proposals to make on the EU draft
regulation for paediatric drugs, all aimed at refocusing the text on the
claimed public health objective. Amendments corresponding to each proposal
will be put by the Forum before the text is examined by the European
Parliament and Council.

Preliminary note: the concept of marketing authorisation for paediatric use
has always existed

It has always been possible to market drugs specifically designed for
children, and also drugs for use by both adults and children (sometimes
different preparations, dose strengths or formulations). Many companies
have marketed paediatric medicines in Europe without being specifically
encouraged to do so. And regulatory agencies have not expressed the opinion
that the marketing applications for these drugs are particularly
The concept of paediatric drugs is therefore not a new one. What is sought
now is a new impetus for paediatric research, aimed at developing drugs for
unfulfilled needs.
The announcement of a "Medicines Investigation for the Children of Europe"
(MICE), on the use of drug substances not covered by patents, is therefore
particularly welcome. Surprisingly, however, this initiative is reported in
the presentation of the draft regulation on paediatric drugs but not in the
main body of the text.
The Medicines in Europe Forum proposes that an article of the regulation
should explicitly deal with the launch of the MICE programme, specifying
the timetable and public funding modalities, and taking into account other
existing EU programmes.  (Amendment 1 proposed by the Forum)

The starting point must be the real needs of children who currently lack
appropriate treatments

According to the European Commission's communiqui presenting the draft
regulation, the objective is 3to improve the health of European children
)2. If this is indeed the objective, then there is no need to increase
the number of paediatric drugs available in fields already covered by
adequate preventive or curative methods, or to encourage pharmaceutical
firms to create spurious needs, as they do for adults. The objective should
rather to encourage and facilitate the development of preventive and
curative means for specific areas in which children and caregivers have no
options whatsoever.

Most European children are in good health and do not need new drugs. Most
of the 100 million children living in the European Union are in good
health, thanks notably to antenatal and postnatal monitoring, vaccination,
and access to clean drinking water, and many hardly need drugs at all. The
priority for such children is primary prevention, including dietary
measures, to avoid obesity and the risk of diabetes for example.
Many childhood health problems necessitating drug therapy are covered by
products already available on the European market. There is no "therapeutic
desert", contrary to some media claims surrounding the launch of the
European initiative on paediatric medicines. Some drugs are excessively
used, or poorly used: excessive use of antibiotics in some countries
increases the risk of bacterial resistance; antiasthmatics are sometimes
prescribed at increasingly high doses, after approximate diagnoses, with a
risk of adverse effects; antidepressants are increasingly used in children,
with a risk of self-harm and even suicide; while methylphenidate is
increasingly used even when the diagnosis of hyperactivity is poorly
established. In such areas the priority is to improve the rational use of
existing treatments.

Don't confuse pharmaceutical form and complex clinical evaluation. For some
age groups we still lack appropriate paediatric forms, dose strengths or
preparations based on substances with a positive balance of benefits versus
harm in children. Development of well-adapted drugs must be encouraged in
these situations. This is based on pharmaceutical technology or
pharmacokinetic studies, but does not require further clinical evaluation.
It is therefore relatively cheap.
Drugs are used empirically in other groups of children, without relevant
clinical evaluation. Intensive fundamental research is needed in other
areas in which the underlying disease mechanisms are unknown and no
effective treatments are available. Research and paediatric evaluation
requires in these circumstances more human and financial resources and
should be strongly encouraged.
The specific needs of particular groups of children must therefore be
precisely identified in order to prioritise available resources and to find
solutions as rapidly as possible.

Providing for a well-conducted inventory. The draft regulation does not
call for a preliminary identification of needs. The principle of an
3inventory2 (and not a true analysis of needs) only appears in article 41
of a draft that counts 56 articles. Article 41 stipulates that the
Paediatric Committee will be charged with compiling this inventory, and it
will also examine marketing applications. The Committee9s affiliation to
the European Medicines Evaluation Agency (financed mainly by pharmaceutical
firms) will be made official. Thus, the same authority will be required to
make an inventory of public health needs, and to act as a service provider
for pharmaceutical firms. Indeed, marketing authorisation has become over
the years a service to industry. In addition, according to articles 41 and
42, the inventory will be based on data collected in Member States on
3existing uses of medicinal products in the paediatric population2. This
data collection is clearly necessary, and has been underway for several
years, but not all habits are well founded. Common practices must be
compared with the most reliable international data, and especially with
epidemiological data.
The Medicines in Europe Forum considers that this inventory of needs must
be launched immediately (without waiting the three years stipulated in
article 41) by a publicly funded, independent scientific authority
including, in addition to paediatricians, public health specialists and
epidemiologists, general practitioners and specialists in other fields
involved in child management, representatives of parent organisations,
health insurers, and specialists in pharmacovigilance. This inventory
should be regularly updated and establish a list of important needs towards
which research efforts should be oriented by providing incentives for both
public research institutions and private companies.
The Forum proposes that article 1 of the regulation, which mentions the
3specific therapeutic needs of the paediatric population2, present the
inventory of needs (currently in article 41) as the framework on which
incentives for the development of paediatric drugs should be based.
(Amendment 2 of the Forum)

Comments on the proposed technical measures: making resources available for
real needs; preventing abuses

The European Regulation on orphan drugs, which has been in effect for 4
years, was designed to promote the development of drugs for patients with
rare diseases and no available treatments. Some positive effects have
already been felt: small groups of patients now benefit from drugs that
improve their daily lives, even if they are not curative. But there have
also been negative effects, such as orphan drug status (and high prices)
being granted for drugs used to treat far larger patient populations than
initially intended; widely used and profitable drugs (such as celecoxib or
sildenafil) for which companies have requested orphan drug status in other
indications; and flawed examination of some marketing applications (e.g.
The Medicines in Europe Forum considers that the regulation on paediatric
drugs should take into account problems encountered with the regulation on
orphan drugs, and proposes the following modifications or precisions.

Transparency of procedures and decisions. Regulation 726/2004 on European
marketing authorisation offers major guarantees with regard to data
transparency and access, even if they are still inadequate in the field of
pharmacovigilance. The draft regulation on paediatric drugs mentions
Regulation 726/2004 and should therefore offer the same guarantees.
However, some of the draft articles are not sufficiently clear or precise.
Draft article 5, which deals with the functioning of the Paediatric
Committee of the European Medicines Evaluation Agency, stipulates that if a
consensus opinion is not reached, 3the opinion will consist of the position
of the majority of members and divergent positions, with the grounds on
which they were based2.
The Forum considers that a clearer wording is needed, in order to guarantee
that voting details are made public at the same time as the final decision.
(Amendment 3 of the Forum)
Draft article 15 indicates that the European Medicines Evaluation Agency
shall maintain a list of all waivers, i.e. all cases in which a company
does not need to provide paediatric data because the drug has no interest
for children. This list, being an administrative document belonging to the
Agency, should theoretically be made public, but the draft does explicitly
mention this requirement.
The Forum considers that the article should contain words to the effect
that This regularly updated list shall be made public. (Amendment 4 of the

Precise endpoints. The presentation of the draft regulation states that:
"studies must be done only if one can expect a therapeutic advantage for
children (avoiding dual use)". But according to article 7.1.d of the draft
regulation, the Paediatric Committee that evaluates the paediatric
investigation plan will offer an opinion 3on the quality, safety and
efficacy2 of the drug. Thus, the body of the text no longer contains the
notion of demonstrating therapeutic advance for the children concerned.
According to the draft text, if a therapeutic advantage over existing means
was sought but not demonstrated, the Committee would nevertheless be able
to give a favourable opinion, considering the drug to be effective and
safe. True, article 7.2 stipulates that the Committee will examine 3whether
or not any proposed studies can be expected to be of significant
therapeutic benefit to the paediatric population2 and article 12.1.c waives
the need to present paediatric data if 3the specific medicinal product does
not represent a significant therapeutic benefit over existing treatments
for paediatric patients", but the word "significant" is vague.
The Forum considers that there is no reason to reward a company for a drug
that offers children no advantages relative to existing therapeutic
options. The risk is that in the paediatric setting, as in adult medicine,
there will be an increase in very similar drugs, creating a source of
confusion, over-consumption, and harms. Added therapeutic value must be
taken into account when rewarding the development of a paediatric drug.
(Amendment 5 of the Forum)

Time allowed for application examination. Draft article 18 is precisely
worded with regard to the time allocated for examining the paediatric
investigation plan, and on its prolongation if supplementary information is
requested. In contrast, draft article 23, concerning modifications of these
investigation plans, is far too vague. Paediatric trials are difficult to
conduct, and investigation plans often need to be modified as a result. The
Paediatric Committee must have sufficient time to examine proposed
modifications and their possible consequences for the quality and
pertinence of the paediatric investigation.
The Forum considers that precise time periods must be added to article 23.
(Amendment 6 of the Forum)

Time to effective drug availability. Draft article 34 indicates that, when
a drug has already been placed on the market in other indications (in
adults), and the company is granted a paediatric indication, it must place
the drug with the paediatric indication on the market within two years
following the authorisation. But this period makes no sense if the
paediatric authorisation was granted because the drug offers children an
advantage. Marketing should take place as soon as possible once
authorisation is granted.
This article needs to be clarified. (The Forum requests clarification)

Public access to evaluation data. Draft article 29.1 stipulates that the
results of studies done according to the paediatric investigation plan
3shall be included in the summary of product characteristics and, if
appropriate, in the package leaflet of the medicinal product, whether or
not all the paediatric indications concerned were approved2. It is indeed
important for health care professionals and patients to have access to
evaluation data, but this wording calls for two comments.
On the one hand, the same information (results of clinical trials, but also
the trial protocols) must be made public and the words 3if appropriate2
must be removed. Even if the wording of a package leaflet must be clear,
concise and comprehensible, it must not hide some of the data.
In addition, data that accompanied a successful marketing application
should be clearly distinguished from data provided in support of
unsuccessful applications. The current trend is for companies to exploit
all their data for promotional purposes, through ambiguous and blurred
presentation of the different sections of summaries of product
The Forum considers that article 29.1 must be more precisely and strictly
worded. (Amendment 7 of the Forum)

Reinforced pharmacovigilance. The presentation of the draft regulation is
intended to reassure the public that pharmacovigilance of paediatric drugs
will be reinforced. But draft article 35 relating to pharmacovigilance
mentions few new measures relative to what already exists for drugs used in
The applicant is simply required to detail (...) the 3measures to ensure
the follow-up of efficacy and possible adverse reactions2. The competent
authority can also demand specific post-marketing studies, or a 3risk
management system2. Draft article 35.4 states that the European Medicines
Evaluation Agency will be charged with establishing guidelines relating to
implementation of this article.
The Forum considers this article far too vague. Pharmacovigilance affairs
are on the increase, and this call for a real change in attitudes leading
to reinforced surveillance and prevention of adverse effects. The planned
guidelines should be integrated now into the draft regulation, and all
short-term and long-term demands accompanying marketing authorisation of
paediatric drugs must be made public. (Amendment 8 of the Forum)
Another article should deal with the collation of adverse events during
clinical investigation, and with the public accessibility of these data
once the drug is marketed. (Amendment 9 of the Forum)
Finally, article 33 of the draft regulation, concerning the identification
of drugs for paediatric use as such on the packaging, should include an
obligation to clearly mention warnings and treatment precautions on the
packaging when the drug exposes to serious adverse effects. (Amendment 10
of the Forum).

Financial incentives in line with research expenditure. Close examination
of evaluation data of paediatric drugs already available on the European
market shows very large variations. In some cases the company only
manufactured a pharmaceutical form and conducted a bioequivalence study.
Others undertook more or less complex clinical trials of various sizes and
Research efforts should be rewarded financially, but this reward must be
proportional to the work actually undertaken. A levelling of rewards, as
anticipated in the draft regulation (an extra 6 months of data protection
for drugs that are still protected, an extra 2 years for orphan drugs
(already protected for 10 years), and 8 + 2 years for drugs that are no
longer protected) carries a double risk: first, a bias in favour of drugs
with the biggest sales figures, which are still protected and whose
manufacturers wish to extend the period of data protection; and a trend
towards lower-quality evaluations.
The Forum considers that draft articles 36, 37 and 38 should include
measures aimed at fine-tuning rewards according to the paediatric
investigation plan rather than the global sales figure. (Amendment 11 of
the Forum)
For the record, the Forum reminds that, in article 14.11 of Regulation
726/2004 (to which article 38 of the project refers), the lengthening of
the duration of data protection for new indications only applies if the
indication is considered to offer 3a significant clinical benefit in
comparison with existing therapies2. This principle should also apply to
new paediatric indications.
The Forum also considers that, if companies continue to demand more than
the financial incentives currently proposed, as suggested by recent
position statements from bigpharma representatives, then we will have
reached the limits of confiding drug research to the private sector.
Available incentives will in this case have to be redirected towards public
research institutions. At all events, research incentives must be
attributed in total transparency, and the results of the research thus
funded must be analysed in the same way.

In conclusion

The Medicines in Europe Forum wishes to underlines that, while the draft
regulation seeks to answer a true need, which is limited in scope but
important, it will be necessary to begin by analysing the precise needs of
European children and their caregivers, and to define priorities. R&D
incentives will have to be attributed according to these priorities. They
should be open to both the public and private research sectors, and be
proportional to real research and development spending. Research must be
done in strict transparency, especially regarding adverse effects that
occur in clinical trials, and that should be proactively detected.

The Medicines in Europe Forum
20 December 2004

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