20th REPORT: PAEDIATRIC MEDICINES: PROPOSED
EU REGULATION
Letter from Rt Hon Jane Kennedy MP, Minister
of State, Department of Health to the Chairman
I am pleased to attach the Government response
letter in respect of the House of Lords European Scrutiny Committee's
report on the European Commission's proposals for a regulation
on medicines for paediatric use.
25 March 2006
Government Response
INTRODUCTION
1. The House of Lords European Union Committee
(Sub-Committee G) published its report Paediatric Medicines:
Proposed EU Regulation on 2 February 2006. This response sets
out the Government's position on the recommendations contained
in that report.
2. The report follows an Inquiry undertaken
by the Committee to examine the European Commission's proposals
for a Regulation on medicinal products for paediatric use (COM
2004 599 final).[19]
The Commission's formal proposals were adopted on 29 September
2004. Negotiations on the proposals began in the Council in October
2004 and the Department of Health (DH)/Medicines and Healthcare
products Regulatory Agency (MHRA) are leading in negotiations
in Europe for the Government.
BACKGROUND
3. Increasing access to paediatric medicines
which have been evaluated to the same standards of safety, quality
and efficacy as those available to adults has been a concern in
the UK for a number of years. In the UK, steps have been taken
at a national level within the existing regulatory framework to
produce, in the short to medium term, a measurable increase in
appropriately labelled and formulated medicines for children,
to increase information on paediatric use of medicines for prescribers,
carers and patients and to facilitate the conduct of paediatric
clinical trials. The Government considers, however, that a pan-European
solution is required to address the current unacceptable situation
and has been supportive of the Commission's initiative to develop
a legislative proposal.
4. The Commission's proposed Regulation
on medicines for paediatric use was developed in response to concerns
expressed by all Member States, including the UK, which resulted
in a Council Resolution of December 2000 which called on the Commission
to develop proposals in the form of incentives and regulatory
measures to ensure that all medicines are adapted to meet the
specific needs of the paediatric population.
5. The proposals recognise the need for
a regulatory approach which includes both incentives and requirements
to ensure that new medicines for children and medicines already
on the market meet the specific needs of the paediatric population
while ensuring that children are not subjected to unnecessary
clinical trials or delaying the authorisation of medicines for
adults. The proposals aim to strike a balance between improving
the availability of medicines licensed specifically for paediatric
use and providing the stimulus for the pharmaceutical industry
to undertake the necessary research. The Government's view is
that the proposed Regulation will be key to addressing the current
unacceptable situation whereby more than 50% of all medicines
used to treat children in Europe have not been tested for specific
use in children.
6. The proposed Regulation will be adopted
though the co-decision procedure. Political agreement was reached
on the draft Regulation at the Health Council in December 2005
under the UK Presidency. The next step is for the European Parliament
to consider the proposal in its second reading. It is hoped that
a common position will be achieved in the first half of 2006 and
that the Regulation may be in place by around the end of 2006.
7. For ease of reference, we have numbered
the Committee's recommendations to reflect the sequence in which
they appeared in the Conclusions and Recommendations section of
the Committee's report (pages 41- 43). Where different recommendations
address overlapping issues we have provided a single overarching
response.
CHAPTER 3—THE
NEED FOR
THE REGULATION
1. We conclude, in principle, from the evidence
we have had that there is an overwhelming and urgent need to take
effective action at European level to govern clinical trials in
children and the authorisation of medicinal products for paediatric
use with the minimum of delay.
This Conclusion is consistent with the Government's
view. Before a medicine is authorised for use in adults, the product
must have undergone extensive testing including pre-clinical tests
and clinical trials to ensure that it is safe, of high quality
and effective. In contrast, most medicines used to treat children
are not studied and licensed for use in children. This has been
of concern to the Government for a number of years and we have
encouraged the Commission to bring forward legislative proposals
in this area.
CHAPTER 4—ETHICAL
CONSIDERATIONS
2. We conclude that the Clinical Trials Directive
is an appropriate basis for this Regulation.
3. We recommend that, in drawing up the guidelines
underpinning the Clinical Trials Directive, the Government should
ensure that particular attention is paid to the rights and capacity
of children to give informed consent to trials. The guidelines
must cover adequately and clearly the vulnerability of children,
the possibility of conflict between the consent of parents and
children involved in trials, the definition of informed consent
and the distinction between consent and acquiescence in circumstances
which are likely to arise during trials involving children, as
well as the extent to which any trials concerned might benefit
the child in question.
The Clinical Trials Directive (2001/20/EC)[20]
is not the basis for this Regulation. That Directive does, however,
provide the legal text which sets out the requirements for conducting
clinical trials and in the recitals to the proposed paediatrics
Regulation there is a specific cross reference to the Clinical
Trials Directive, making it clear that the controls and monitoring
of studies in children conducted in the EU must comply with that
Directive.
The Government believes that the protection
of those participating in clinical trials must be the over-riding
priority and believes that the safeguards laid down in the Clinical
Trials Directive, including the specific requirements for conducting
clinical trials in children as well as the proposed measures contained
in the Commission's proposals, provide a secure framework to ensure
that the health, welfare and rights of children participating
in clinical trials are protected. Obtaining informed consent from
a person with parental responsibility or a legal representative
is a pre-condition of a child's inclusion in a trial. However,
it does not determine inclusion in a trial. That depends on a
number of other factors including consideration of any views expressed
by the child.
The European Commission, in consultation with
Member States, is preparing a guideline on the ethics of conducting
clinical trials in children. It has asked the Ad Hoc Group on
Clinical Trials, which has prepared guidance on the Clinical Trials
Directive, to prepare a draft guideline for public consultation.
The Government will make every effort to ensure that the guideline
covers:
— rights and capacity of children to
give informed consent,
— vulnerability of children;
— possibility of conflict between the
consent of parents and children involved in trials;
— the difference between consent and
acquiescence; and
— the extent to which the trial might
benefit the child concerned.
Officials from the MHRA will represent the Government's
policy aims within the Ad Hoc Group. It is intended that the guideline
will be in place when the proposed Regulation on medicines for
paediatric use comes into force.
4. We conclude that, in many other respects,
the ethical validity and effectiveness of the Regulation will
depend as critically on the guidelines to be developed as on the
text of the Directive itself. While detailed discussion of such
aspects is appropriate for legal, medical and pharmaceutical experts,
who must be adequately consulted, we recommend that the underlying
issues of public policy should be given wider attention and political
oversight. We therefore welcome the Minister's agreement that
the relevant officials should give us on-the-record briefing on
the progress made in developing those guidelines at an appropriate
time after the Directive has been agreed by the Council.
5. We recommend that once the guidelines are
drawn up the Government should ensure that they are fully understood
by the medical and pharmaceutical professions and explained to
the general public.
6. We further recommend that the Government
should ensure that the guidelines are kept fully up to date in
line with changes in medical and scientific knowledge and practice.
The guidelines underpinning the Regulation will
be important in setting out how it will work in practice. The
Government has given an undertaking to update the committee on
developments at the appropriate time. We expect specific guidance
to be developed in a number of areas including, for example, the
rules of procedure for the proposed paediatric committee and guidance
on the required format and content of an application for agreement
of a paediatric investigation plan. The Commission will have responsibility
under the comitology procedure for developing the guidelines in
consultation with Member States. The Government will ensure that
the guidelines are available to all stakeholders including healthcare
professionals, patient organisations and the pharmaceutical industry.
It is established practice for European guidelines resulting from
pharmaceutical legislation to be updated regularly in the light
of developments in medical and scientific knowledge and practice
and the Government will ensure that they are.
CHAPTER 5—INFORMATION
7. We recommend that the Clinical Trials Database
should contain full details of all paediatric clinical trials,
whether terminated prematurely or not. The database should be
publicly available as a vital safeguard not only for those who
might be involved in clinical trials but also for the medical
profession and the paediatric population of Europe as a whole.
This principle must be assured in the Regulation itself and in
any guidelines developed from it.
The Government agrees that the database established
under the Clinical Trials Directive should contain full details
of paediatric clinical trials conducted in the Community. In order
to increase the availability of information on the use of medicines
in children, and to avoid unnecessary duplication of studies in
children, it is proposed that information concerning paediatric
clinical trials entered into the database, as well as the details
of the results of all paediatric clinical trials submitted to
the competent authorities, should be accessible to the public.
There may be some information that cannot be made public or cannot
be made public immediately because of considerations relating
to commercial confidentiality. The Commission will draw up guidance
on which data would be entered on the database and which elements
can be made accessible to the public.
8. We recommend that the Government should
give further and serious consideration to the proposal that products
should be labelled in a way which indicates their suitability
for use in children.
The proposal regarding labelling has changed
in the latest text of the Regulation. An abstract symbol, to be
agreed by the Commission on a recommendation from the paediatric
committee, will appear on the package label of all medicines authorised
for paediatric use. Its meaning will be explained in the patient
information leaflet. The symbol will not denote a particular age
group. The Government will, through membership of the committee,
have an input into the selection of a suitable symbol.
9. It is abundantly clear from our evidence
that children are not just young adults: their reaction to drugs
varies considerably in relation to age and other factors and the
newly-born are particularly vulnerable. We therefore recommend
that any labelling scheme that is devised must take full account
of this and make plain the risks of using products without consulting
the relevant product information, especially for products which
are available without prescription. Product information should
also be summarised in clear, non-scientific language that leaves
no doubt whatsoever about the risks of misuse and the need to
follow carefully the dosage information.
The Government supports the Commission's proposal
for identifying products that have been studied in children. It
is proposed that a symbol will be placed on the label of all medicines
authorised for paediatric use whether they are supplied on prescription
or not. The meaning of the symbol will be explained in the package
leaflet. The Government does not believe that age specific symbols
are required. The symbol will be selected by the paediatric committee
within one year of the Regulation coming into force. The Government
will, through membership of the committee have an input into the
selection of a suitable symbol. The proposal also includes provisions
to include more information on paediatric use in the product information,
including advice on when and why not to use a product in a paediatric
age group.
Medicines labelling and patient information
leaflets are already required to be set out in a manner which
is accessible to the patient/carer so that the medicine can be
used safely and effectively. In July 2005, the MHRA and the then
Committee on Safety of Medicines (CSM) jointly published guidance
for those involved in writing information for patients/carers
on how best to meet their needs (Always Read the Leaflet—Getting
the Best Information with Every Medicine). Included within this
guidance is a particular section concerned with meeting the needs
of specific patient groups including children and young people
and how their communication needs can be met. The MHRA has recommended
this guidance to the pharmaceutical industry and will monitor
and update progress on this initiative, reporting to the Commission
on Human Medicines in due course.
CHAPTER 6—MECHANISM
FOR IMPLEMENTING
THE REGULATION
10. We conclude that the European Medicines
Agency (EMEA) is the appropriate body to oversee and co-ordinate
the tasks envisaged by the proposed Directive. We welcome the
Minister's assurances that the EMEA should be sufficiently resourced
to carry out this task and that experience suggests it will work
smoothly and effectively with the health services and agencies
of Member States in doing so. But we recommend that these aspects
should be kept under close review by the Government once the Directive
enters into force.
11. We conclude from the evidence we have
been given that the overall composition of the paediatric committee
is about right, we fear that any increase in the size of its permanent
membership might run the risk of making it unwieldy.
12. But, because the effective functioning
of the Committee is crucial to the success of the Directive, we
recommend that the Government should keep the composition of the
Committee under review and ensure that it draws, where necessary,
on relevant available ethical and practical expertise from Member
States which may not be directly available through the Committee's
own membership.
The EMEA has a proven track record with 10
years experience of overseeing and co-ordinating European pharmaceutical
legislation. The agency operates in close co-operation with the
regulatory authorities in Member States and their networks of
national experts. The members of the proposed paediatric committee
may be supported by additional national experts, as necessary.
As well as providing members for the proposed paediatric committee,
the national regulatory authorities will be involved in, amongst
other things, providing regulatory and scientific advice on paediatric
drug development, assessing paediatric data, setting up clinical
trials networks, and providing information on existing use of
medicines in children. The Government agrees that all aspects
of the Regulation, including the proposals in respect of the paediatric
committee and the EMEA, should be kept under review. It is proposed
that the operation of the Regulation will be reviewed within six
years of entry into force.
13. We are unable to judge from the limited
evidence and time available to us whether the proposal for funding
research into paediatric use of off-patent medicines throughout
the Community's research frame work programmes will be adequate.
Nor are we able to assess the need for a separate Community-funded
research programme on the lines of the Medicines Investigation
for the Children of Europe (MICE) proposal. But we recommend that
both aspects are adequately addressed, in consultation with interested
parties, when the Commission review the working of the Regulation.
The Government accepts this recommendation
and believes that this will need to be considered when the Commission's
review of the Regulation takes place. The Government believes
there is a need for a study programme for research into paediatric
use of off-patent medicines and at this stage takes the view that
this can be achieved through the Community's research framework
programme.
CHAPTER
7—REWARDS
AND INCENTIVES
14. We recognise that the package of incentives
and rewards proposed in the Regulation are a political compromise,
based on the acknowledged need to provide incentives and the apparent
success of the US model. But we conclude that they are essentially
a leap of faith: it is impossible to judge from the information
we have been given whether these arrangements are likely to provide
the necessary incentives to industry, whether they are likely
to be equitable and proportionate, or whether they may give rise
to excessive profits, penalise the health service of Member States
or create unacceptable disadvantages for the manufacturers of
generic products.
15. We accept that a political compromise
is necessary for the time being to launch the Regulation in the
hope that it will bring the desired benefits for the children
of Europe at a reasonable cost. But we recommend that the Government
should continue to press the Commission to ensure that a full
economic review of these proposals is made as soon as possible.
16. If the Commission are unable to provide
such a review within six years of implementation, as required
by Article 49 of the Regulation, we recommend that they should
be required to explain to the satisfaction of the Council why
it would be premature too do so at that stage and to ensure that
it is done as soon as possible after that.
17. We also recommend that our successors
should subject that review to very rigorous examination when it
is submitted for Parliamentary scrutiny.
18. In the meantime, we recommend that the
Government should make every effort to improve on the adequacy
of the estimates of costs and benefits produced in the regulatory
impact assessment as soon as it is practicable to do so and to
submit the results to Parliamentary scrutiny.
The Government welcomes the support of the committee
on its position for incentivising the pharmaceutical industry
to carry out paediatric clinical trials. The Government believes
that the incentive should be fair but not excessive, and supports
the political position agreed at the Health Council in December
for a six-month extension of the supplementary protection certificate.
As demonstrated by the range in the estimated
impact of the Regulation in the Rand Europe document and the Government's
partial regulatory impact assessment it is not possible to accurately
estimate the impact on the NHS at the present time. This information
will not be available until medicines start to go through the
process set out in the Regulation and come on to the market. This
is why the Government argued and secured a review of the economic
and health benefits of the Regulation to take place six years
after it has come into force. However, if there is not sufficient
data available at that time this review will be carried out within
ten years of the Regulation coming into force. This position was
agreed at the December Health Council, and the Government will
continue to support this position.
The Government supports the committee's recommendation
to update the partial regulatory impact assessment. Once sufficient
information is available to do this, the Government will submit
it to the committee for scrutiny.
CHAPTER 8—LEGAL
BASE
19. In principle, we continue to believe that
the Government should take a robust and consistent line in opposing
proposals by the Commission which are, in the Government's view,
brought forward for an inappropriate legal base. In this particular
instance, in light of the overriding importance of the proposal
and the need to make rapid progress in implementing it, we conclude
that the Government is justified in agreeing to the present proposal
with a Minute Statement recording its objection to the legal base.
The Government welcomes the committee's endorsement
of its position in relation to the legal base for this proposal
and is grateful that the committee was able to grant scrutiny
clearance before the Health Council on 9 December 2005. The committee
will be aware that the Government's view was that Article 95 of
the Treaty was not an appropriate legal basis for this Regulation
and that Article 308 should have been used instead for the reasons
invoked in case C-66/04 UK v EP and Council (the smoke
flavourings case). Judgement in that case was given on 6 December
2005. The UK's arguments on the correct legal base for establishing
a centralised procedure were rejected. Given what the Court said
about the breadth of Article 95 and the measure of discretion
conferred on the Community legislature as regards its use and
the fact the proposed Regulation does not actually set up a new
agency, but rather establishes a new committee within an existing
agency, similar to the situation in the smoke flavourings case,
the Government withdrew its objection to the legal base for the
Regulation at the Health Council on 8-9 December 2005 and accordingly
did not enter a minute statement. The Government will continue
to take a robust line on legal base issues in the future.
Letter from the Chairman to Rt Hon Jane
Kennedy MP
Thank you for your letter dated 25 March enclosing
the Government Response to the Report of the Committee's Inquiry
into the above Proposal, which was received shortly before the
House rose for the Easter Recess. The Response was considered
by Sub-Committee G on 27 April.
As you know, although the Report was only made
for information, Baroness Thomas has put down a Question related
to the Report which is expected to be debated in due course. We
propose to publish the Government's Response in advance of that
Debate.
Before doing so, however, we wish to draw your
attention to the enclosed submission of additional evidence from
the Association of the British Pharmaceutical Industry (ABPI)
which was only received on 18 April. A copy has already been sent
to the responsible officials at the MHRA.
As you will see, the ABPI are making representations
about what they regard as the adverse effect of the two-year notice
period required for applications for the six-month extension to
the Supplementary Protection Certificate. They are asking for
transitional arrangements that would modify the proposed Regulation.
This follows informal representations made to the Committee by
representatives of two pharmaceutical companies, AstraZeneca and
Novartis, after the Report was published. But it was not raised
in the evidence given to the Inquiry by the ABPI or any other
witnesses.
In the absence of any other evidence we are
unable to take a view on what the ABPI have now said. But we believe
that their submission is sufficiently important for it to be treated
as supplementary evidence which should be made public and that
the Government should be invited to submit views on it. We therefore
propose to publish the ABPI submission together with the Government
Response to the Inquiry before the Debate. It would therefore
be most helpful if you could let us have the Government's response
to the ABPI submission by Friday 19 May. That would enable us
to publish both documents shortly afterwards in the hope that
the Debate might be held sometime in June.
I hope this is acceptable to you and look forward
to your reply.
27 April 2006
19 Full title of the proposal is "Proposal for
a Regulation of the European Parliament and of the Council on
medicinal products for paediatric use and amending Regulation
(EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No
726/2004. Back
20
Directive 2001/20/EC of the European Parliament and of the Council
of 4 April 2001 on the approximation of the laws, regulations
and administrative provisions of the Member States relating to
the implementation of good clinical practice in the conduct of
clinical trials on medicinal products for human use. Back
| 
