14 Regulating clinical trials
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12751/12
COM(12) 369
+ ADDs 1-3
| Draft Regulation on clinical trials on medicinal products for human use, repealing Directive 2001/20/EC
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| Legal base
| Articles 114 and 168(4)(c) TFEU; co-decision; QMV
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| Department
| Health |
| Basis of consideration
| Minister's letter of 21 January 2014
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| Previous Committee Reports
| HC 83-xxiii (2013-14), chapter 7 (4 December 2013);
HC 83-v (2013-14), chapter 4 (12 June 2013);
HC 86-xxxix (2012-13), chapter 7 (24 April 2013);
HC 86-xvi (2012-13), chapter 7 (24 October 2012);
HC 86-xi (2012-13), chapter 9 (5 September 2012)
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| Discussion in Council
| No date set
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| Committee's assessment
| Politically important
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| Committee's decision
| Cleared |
Background and previous scrutiny
14.1 Clinical trials provide essential
information on the safety, efficacy and therapeutic benefits of
particular drug treatments and increasingly involve participants
at different trial sites across a number of Member States. Since
2004, the authorisation and conduct of clinical trials within
the EU has been regulated by the Clinical Trials Directive.[66]
The Commission believes that the Directive has improved the safety
and ethical soundness of clinical trials across the EU, as well
as the reliability of the data obtained. It also acknowledges
that, since its entry into force, the Directive has increased
costs and contributed to a decline in clinical trials in the EU,
describing it as arguably the most heavily criticised piece of
EU legislation in the area of pharmaceuticals.[67]
14.2 The draft Regulation would repeal
the Directive, introduce a new and less costly authorisation procedure,
and seek to ensure that the rules governing the conduct of trials
are differentiated to take account of the degree of risk associated
with each trial. An EU portal, linked to a database, would provide
a single point of entry for the submission of all the information
needed to assess the therapeutic and public health benefits of
a proposed clinical trial, as well as potential risks to patients
taking part in the trial. The EU portal would be used for all
clinical trials. For trials involving more than one Member State,
a single "reporting Member State" would be responsible
for making an initial assessment, taking into account any views
communicated by other Member States in which the clinical trial
is proposed to take place. Each Member State would be responsible
for assessing those aspects of the draft Regulation which the
Commission describes as "intrinsically national, ethical
or local" — these include the well-being of those participating
in the clinical trial and requirements for obtaining their informed
consent, the suitability of the clinical trial site and of those
conducting the trial, and compensation arrangements.
14.3 In an attempt to reduce the financial
burden associated with clinical trials, the Commission draws a
distinction between "low intervention" clinical trials
(where the risk to participants only marginally exceeds that already
inherent in normal clinical practice) and others where there may
be additional risk. For the latter, the Commission has proposed
the introduction of a national indemnification mechanism, which
would operate on a not-for-profit basis, in order to help non-commercial
sponsors, such as academics involved in medical research, to obtain
the necessary insurance cover for clinical trials.
14.4 The Government welcomes the draft
Regulation, supports the "proportionate and risk-adapted
approach" to clinical trials proposed by the Commission,
and considers that it has the potential to reduce regulatory,
administrative and financial burdens. Whilst endorsing the use
of a single EU portal for all clinical trial applications in the
EU, the Government has pressed for a clearer description of how
the single authorisation procedure would work, focusing in particular
on the relationship between the reporting Member State and other
Member States likely to be involved in a clinical trial. It opposes
the introduction of a national indemnification mechanism on the
grounds that the commercial insurance market for clinical trials
works well in the UK. Our earlier Reports provide a detailed
overview of the draft Regulation, the Government's position and
the views of stakeholders.[68]
14.5 There is a broad consensus on the
need to change the existing regulatory framework for clinical
trials within the EU and we are grateful for the Government's
progress reports on the negotiations. When we last reported on
the draft Regulation, we noted that trilogue discussions between
the Council, European Parliament and Commission were expected
to conclude before the end of 2013 and asked the Minister (Earl
Howe) to provide further information on:
· the changes that have been
made to the procedure for authorising clinical trials (including
the relevant timescales) and, in particular, how the Member State
carrying out the initial clinical assessment will take into account
the views of other Member States in which a clinical trial is
proposed to take place;
· whether the Commission's
proposal for the introduction of a national indemnification mechanism
for certain types of clinical trials will be retained in the draft
Regulation or, if not, what will replace it;
· any other significant changes
to the Commission's original proposal; and
· his assessment of the impact
that the changes are likely to have on the authorisation, conduct
and publication of the conclusions of clinical trials in the EU,
as well as the availability of clinical trial data.
The Minister's letter of 21 January 2014
14.6 The Parliamentary Under-Secretary
of State for Quality (Earl Howe) tells us that an informal agreement
has been reached on the draft Regulation, following the conclusion
of trilogue discussions in December 2013. He considers that the
compromise agreed meets the Government's negotiating objectives,
represents a significant improvement on the existing Directive,
and will help to make the EU a more attractive place to conduct
clinical research. He asks us to release the draft Regulation
from scrutiny so that the Government is able to support its formal
adoption at a forthcoming Council meeting.
14.7 The Minister describes the main
changes to the Commission's original proposal. Turning first
to the authorisation procedure for clinical trials, he notes:
"The proposed efficiencies
in the authorisation process — worth £595 million in
savings according to the European Commission's impact assessment
— have all remained in the text. These include the EU portal
and database, the single submission, the joint assessment of multi-state
applications and the single decision at national level (combining
the currently separate regulatory and ethics approvals).
"It has been agreed that the
European Medicines Agency (EMA) will be responsible for building
and maintaining the portal and the database and not the European
Commission. The Government supports this because this will allow
Member States to directly influence the development of the IT
systems through the Management Board of the EMA. Because these
IT systems are of critical importance for the implementation of
the Regulation, provisions have been included in the text, on
the basis of a UK proposal, that will allow for an independent
audit of the functionality of the IT systems, commissioned and
reviewed by the EMA Management Board, and that will ensure that
the Regulation will only apply once all necessary IT systems are
fully functional."
14.8 The Minister notes that the Commission's
original proposal contained little detail on the practical operation
of the joint assessment process for clinical trials involving
more than one Member State. This has been rectified in the compromise
text, which establishes three distinct "phases":
· an initial assessment phase
by the designated reporting Member State covering the clinical
aspects of the trial;
· a coordinated review phase
carried out by all Member States involved in the clinical trial;
and
· a consolidation phase in
which the reporting Member State produces a final assessment,
taking due account of any concerns raised by other Member States
and recording how they have been addressed.
14.9 Member States involved in the joint
assessment process are bound by the outcome of the final assessment,
unless they have reason to object on the following grounds:
· participation in the clinical
trial would result in inferior treatment when compared with normal
clinical practice in the objecting Member State;
· participation in the clinical
trial would infringe national laws on the use of human cells,
substances that induce abortion, or narcotic substances; or
· concerns raised during the
joint assessment process which are based on safety and the reliability
or robustness of the data submitted to support the clinical trial.
14.10 The Minister notes that the timelines
for approving clinical trials have been extended (from 41 to 60
days if no questions are raised during the authorisation process,
and from 65 to 91 days if there are questions), but adds:
"Tacit approval (if no decision
is taken within the 60 day period, the authorisation is deemed
to be given), although controversial among Member States, has
remained in the text."
14.11 He continues:
"The Government would have
preferred to have seen timelines closer to the European Commission's
proposal. However, there was very little support from other Member
States for these as the majority thought more time was needed
for the multi-state assessment process and the coordination between
regulator and ethics committees at national level. Although longer
than we would have liked, the Government thinks the agreed timelines
are acceptable given that the timeline includes joint assessment
of multi-state applications and a joint ethical/regulatory decision
at Member State level. UK only trials (approximately 50 percent
of authorisations in the UK) will continue to be authorised well
within the agreed timelines, ensuring that the UK remains competitive
both within the EU and globally."
14.12 The Minister adds that the shorter
timelines envisaged by the Commission for low intervention clinical
trials — those using medicines within the terms of their
existing marketing authorisation or in a way that is evidence
based and poses minimal additional risk to patients — have
been removed. Nevertheless, he concludes that:
"Overall, the authorisation
process for sponsors of clinical trials conducted in the EU will
be much simpler and efficient than it is today. Sponsors will
only have to submit one application for a trial in the EU to the
EU portal where they currently have to submit two applications
in every Member State (to the regulator and the ethics committee).
The joint assessment of multi-state applications within a single
common timeline will benefit sponsors further as will the single
decision at Member State level. This will make it easier to conduct
clinical research in the EU."
14.13 The Minister notes that the draft
Regulation clarifies how the ethical dimension of clinical trials
is to be assessed. He continues:
"The European Commission's
proposal only referred to Member States and not ethics committees
or national competent authorities. This was done to reflect divergent
practices in Member States. In the current text, 'ethics committee'
has been defined and it has been clarified that an ethical review
must be performed and that this must be done by an independent
ethics committee. Where the European Commission proposed to take
the view of at least one patient into account when assessing an
application, this has now been changed to [a] lay person because
it is not always possible to have patients participate in the
assessment."
14.14 Changes have been made to the
provisions of the draft Regulation dealing with informed consent:
"The text has been amended
to reflect that clinical trials on incapacitated subjects and
minors can take place not only when there is direct benefit to
the subject involved but also when there is some expected benefit
to the population represented. In this situation the trial must
only pose minimal risk to and minimal burden on trial subjects
in comparison with the standard treatment.
"The text also introduces provisions
for clinical trials on pregnant and breastfeeding women and provides
Member States the possibility to maintain additional measures
for clinical trials on persons in the military service, persons
deprived of liberty or persons in residential care institutions.
Although the Government believes the existing provisions covered
all of these groups, we see no harm in having these additional
provisions."
14.15 New provision is made for the
introduction of simplified informed consent for so-called "cluster
trials" which only take place in one Member State. The Minister
explains:
"Cluster trials are large scale
trials with medicines used within their marketed authorisation
in which GP practices or hospitals or even regions of the country,
are randomised instead of the patients. The simplified consent
must be in line with national legislation and is subject to review
by an ethics committee."
14.16 The Minister reiterates the Government's
objections to the proposed introduction of a national indemnification
mechanism for certain clinical trials which would have obliged
Member States to "take over the role of private insurers
in insuring clinical trials". He continues:
"The Government has been unable
to support the mechanism because of the flaws in the European
Commission's impact assessment and the lack of evidence found
in the UK that insurance for clinical trial activity is a problem.
Member States unanimously rejected this proposal and this obligation
has now, in agreement with the European Parliament, been removed
from the text. It has been replaced by a general text requiring
Member States to ensure that systems for compensation for damages
suffered by a subject resulting from participation in a clinical
trial are in place. These systems can be either private or public."
14.17 Turning to the transparency of
clinical trial data, an issue we raised in our previous Report
on the draft Regulation, the Minister summarises the outcome agreed
in the compromise text, following negotiations with the European
Parliament:
"As proposed by the European
Commission, all trials conducted in the EU will need to be registered
and a summary of the results will need to be submitted to the
EU portal within one year after the end of the trial. In addition
to this, the structure and content of this summary has now been
included in the annex to the Regulation and the requirement to
include a lay summary has been introduced.
"In addition, clinical study
reports that have been submitted in support of a marketing authorisation
will have to be submitted to the EU database by the applicant
within 30 days after a marketing authorisation has been granted,
the decision making process has been completed or the applicant
has withdrawn the application. The EU database will be publicly
accessible except for when confidentiality is justified on the
grounds of protecting personal data, protecting commercially confidential
information, protecting confidential communications between Member
States or ensuring effective supervision of the conduct of the
trial by a Member State."
14.18 The Minister adds:
"I believe the Regulation will
have a very positive impact for the public on their knowledge
of what clinical trials are actually taking place, because all
trials will need to be registered. In anticipation of the application
of the Regulation, the Health Research Authority (HRA) has already
made trial registration a condition of a favourable ethics opinion.
The availability of summaries of all trials and clinical study
reports where available will also have a great impact on transparency
of clinical trial results. Also as required by the Regulation,
the European Commission will produce a guideline on the formatting
and sharing of raw data on a voluntary basis."
14.19 Finally, the Minister notes that
the draft Regulation includes a clause requiring the Commission
to undertake a review five years after it has become operational.
The review will assess the impact of the Regulation on scientific
and technological progress, provide comprehensive information
on the different types of clinical trials authorised in the EU,
and consider the measures needed to maintain the competitiveness
of European clinical research (accompanied, if appropriate, by
further legislative proposals to update the Regulation).
14.20 The Minister recognises that implementing
the Regulation will present challenges, adding:
"The EU portal and database
will need to be fully functional before the Regulation can apply
and the Government will therefore influence the development of
the IT systems where it can. Also, Member States will need to
ensure that coordination mechanisms are in place between the regulator
and ethics committees and that ethics committees can work to the
agreed timelines. I believe that in the UK, we are in a good
position to do this with the work that the Health Research Authority
(HRA) has been doing on streamlining ethical review and the existing
collaboration between the HRA and the Medicines and Healthcare
Products Regulatory Agency (MHRA)."
Conclusion
14.21 We thank the Minister for providing
a comprehensive update on the outcome of trilogue negotiations
and a copy of the compromise text agreed. We welcome the inclusion
of additional provisions clarifying how multi-State assessments
of clinical trials will be conducted and take due account of the
views of all participating Member States. We note that the Commission's
proposal for the introduction of mandatory national indemnification
schemes to cover claims for damages arising from participation
in a clinical trial has been replaced by a requirement to ensure
that appropriate systems for compensations are put in place in
each Member State. We understand, in light of the responses to
the Government's consultation on clinical trial insurance, that
the compromise agreed is likely to be acceptable to UK stakeholders.
14.22 We particularly welcome the
strengthening of provisions on the transparency of clinical trials
and clinical trial data. The Report on Clinical Trials published
by the House of Commons Science and Technology Committee in September
2013 underlined the importance of clinical trial transparency
and recommended that efforts to increase the availability of clinical
trial data should focus on the provision of information that is
"accessible, assessable, intelligible and usable".[69]
We consider that the compromise text agreed by the Council and
European Parliament goes a considerable way to achieving these
objectives by requiring:
· registration of all applications
for clinical trials to be conducted within the EU in a single,
publicly accessible EU database;
· publication in the same
database of the results of each authorised clinical trial, irrespective
of the outcome of the trial, accompanied by;
· publication of a lay summary
written in plain language that can be understood by non-experts.
14.23 We note, moreover, that Member
States are required to establish "effective, proportionate
and dissuasive" penalties covering, amongst other things,
a failure to comply with the provisions on transparency.
14.24 We are satisfied that the outcome
of negotiations on the draft Regulation has met the Government's
main negotiating objectives and are content to clear it from scrutiny.
In so doing, we draw our Report to the attention of the Science
and Technology Committee.
66 Directive 2001/20/EC, OJ No. L 121, 01.05.2001,
pp. 34-44. Back
67
See p.17 of ADD 2. Back
68
See headnote. The draft Regulation is also considered in some
detail in the Third Report from the Science and Technology Committee,
(2013-14), Clinical Trials, HC 104. Back
69
See HC 104 (2013-14), para 11 of Conclusions and Recommendations. Back
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