Conclusions and recommendations
What are clinical trials?
1. Clarity
in use of the term "clinical trial" is essential. The
establishment of consistent terminology would be an important
first step towards making the UK an easier place to conduct clinical
research. We recommend that the Government agrees a set of simple
definitions for the terms "clinical trial", "clinical
study" and "clinical research" and ensures their
consistent use across the Health Research Authority, Medicines
and Healthcare Products Regulatory Agency, Medical Research Council,
National Institute of Health Research and the NHS. (Paragraph
11)
The European Clinical Trials Directive
2. We
recognise the significant barrier to research posed by the European
Clinical Trials Directive and welcome proposals for a new European
Clinical Trials Regulation. However, we are concerned that a lack
of clarity in the detail of the Regulation could lead to inconsistencies
in its implementation across Member States, and we are not persuaded
that proposals go far enough in ensuring that low-risk trials
are regulated in a proportionate way. We urge the Government and
MHRA to continue engaging at a European level to resolve these
issues and to work together to ensure that, when the resulting
legislation is introduced, the administration of clinical trials
in the UK will be pragmatic and proportionate. (Paragraph 24)
UK regulatory and governance complexity
3. We
commend the establishment of the Health Research Authority (HRA)
and note that feedback on the HRA's performance to date has been
largely positive. However, we are unable to judge whether the
HRA has so far been effective in achieving its objectives, as
the necessary performance indicators are not currently in place.
We recommend that the HRA establishes and publishes a suite of
relevant key performance metrics and targets in its 2014/15 Business
Plan, and monitors performance against these targets annually.
We further recommend that a triennial review of the HRA takes
place no later than December 2014, three years after its creation
as a Strategic Health Authority. (Paragraph 31)
4. Over a year after
its creation, some stakeholders (including an academic health
science centre, intended to be a centre of excellence for UK health
research) remained unaware of the function, or even the existence,
of the HRA. Although these stakeholders also bear some responsibility
for their own awareness of such developments, we consider that
the HRA should now place greater emphasis on engaging with the
clinical research community and raising the profile of its work.
The HRA should detail in its response to this Report how it intends
to do this. (Paragraph 32)
5. We welcome moves
by the HRA to streamline NHS governance arrangements and stress
the importance of this initiative, which, in our view, should
be given the highest priority. Following completion of the feasibility
study, we recommend that a timeline detailing the next steps be
published as part of the HRA's response to this Report. The Government
should assist the HRA in its efforts to meet this priority, including
making additional resources available if necessary. (Paragraph
35)
6. We are disappointed
that the Government has failed to meet its own 2012 deadline for
measuring NHS Trust performance against a 70-day benchmark for
clinical trial initiation and we query whether this target is
realistic in the short-term. We recommend that the Government
updates us on current performance and on how many NHS Trust contracts
now include this benchmark in its response to this Report. (Paragraph
37)
Patient recruitment
7. We
welcome changes designed to make the NHS Constitution more research-focused
and the launch of the Government's OK to Ask campaign. However,
we are cautious of any suggestion that the system, as a result
of this new onus, will automatically act to promote the existence
of and encourage involvement in clinical trials. We recommend
that the Government provides details of how changes to the NHS
Constitution and the OK to Ask campaign have been communicated
and promoted, both within the NHS and to the general public. In
twelve months' time it should publish evidence on how the measures
have affected both public and professional attitudes to, and participation
in, clinical trials. (Paragraph 43)
8. We note the apparent
lack of public confidence in the pharmaceutical industry and are
concerned that this may increasingly pose a barrier to conducting
trials in the NHS. Industry should act to regain trust lost through
past examples of poor behaviour by engaging more effectively and
transparently with the public in the future. In addition, Trusts
need to do far more to educate patients about the benefits, both
to them and to the wider community, of participating in research
and allowing properly controlled sharing of patient data. (Paragraph
44)
9. We were impressed
by the quality and accessibility of Cancer Research UK's trials
database, which is reflected in the high volume of traffic that
it receives. In contrast, while we are satisfied that the Government
is working to improve and promote its own Clinical Trials Gateway,
we were concerned to find that only 20% of its target users were
aware of its existence as of mid-2012, and that the Minister was
unable to give us a more detailed account of what was being done
to improve this. The Government must improve the Clinical Trials
Gateway and raise its profile with patients, clinicians and the
general public. We recommend that the Government provides details
about how it will achieve this, together with indicative timelines
and targets, in its response to our Report. (Paragraph 50)
10. We consider it
important that the information contained on the Clinical Trials
Gateway is accessible to the lay person, which does not appear
to be consistently the case at present. The Government should
ensure that all trials listed on the Gateway include a plain language
summary written specifically for a lay audience. Where such summaries
are not already in existence, the Government must be prepared
to commit the time and effort needed to create them. Taking into
account the Gateway's current resource levels, we recommend that,
where possible, preparation of a lay summary should be included
as a requirement for publicly-funded trials, but that the Government
remain open to the option of increasing the level of resource
dedicated to the Gateway if necessary. (Paragraph 51)
Clinical trial transparency
11. Clinical
trial transparency is important and greater transparency would
be likely to provide a number of benefits, particularly if applied
retrospectively. However, there are obstacles to achieving this
and the drive for greater transparency must be balanced against
other concerns, particularly the need to protect patient privacy.
Greater disclosure does not necessarily equate to greater transparency
if the information shared cannot easily be understood and we therefore
recommend that efforts to increase the availability of clinical
trial data focus on providing information that is accessible,
assessable, intelligible and usable. (Paragraph 58)
Level 1: Trial registration
12. We
consider universal trial registration to be a crucial step in
increasing clinical trial transparency and believe that all future
trials should be included in a publicly-accessible register. This
is clearly not the case at present, even for trials conducted
in the UK. We recommend that the Government take steps to ensure
that, in future, all clinical trials conducted in the UK, and
all trials related to treatments used by the NHS, are registered
in a WHO-listed primary registry. (Paragraph 63)
13. Since the trials
of treatments currently in use often occurred many years ago,
retrospective disclosure is important if the benefits of clinical
trial transparency are to be realised in the short to medium-term.
Although retrospective trial registration will incur some cost,
we consider that this will be outweighed by the public health
benefit of having a complete picture of the trials conducted on
treatments currently available to patients. The Government should
support the retrospective registration of all trials conducted
on treatments currently available through the NHS and should actively
pursue policies to bring this about. (Paragraph 64)
Level 2: Summary-level trial results
14. We
consider that summary-level results should be made publicly available
for all clinical trials and we welcome the many new media through
which it is now possible to share this information. Nevertheless,
peer review is vital to the reputation and reliability of scientific
research and we deem it appropriate that journal articles remain
the primary instrument for the publication of summary-level trial
results. (Paragraph 68)
15. Many historic
trials remain unpublished, which is far from ideal. However, retrospective
publication of all trials of all treatments currently in use,
while desirable, would almost certainly be unachievable given
the likely time and resources that this would require. We therefore
emphasise again the importance of retrospective trial registration
as a means of providing a vital "index" against which
individual cases of non-publication can be identified and, where
of particular importance, pursued on an ad hoc basis. (Paragraph
69)
16. Given recent changes
to academic publication models, we do not recognise as legitimate
the argument that it is not possible to publish "negative"
results in a peer-reviewed journal and we consider failure to
publish on a timely basis to be poor scientific practice. However,
we are sympathetic to the pressure that scientists are often working
under and therefore we urge the Government and other trial funders
to ensure that researchers are provided with the time and resources
needed to meet their publication obligations. (Paragraph 70)
17. We encourage academic
publishers to remove "Ingelfinger" restrictions on the
pre-publication of summary-level results through media such as
trial registries, in order to facilitate greater openness and
faster access to important scientific data. (Paragraph 72)
Level 3: Clinical study reports
18. It
would be unduly burdensome to mandate that clinical study reports
(CSRs) be produced for non-commercial trials. We also consider
that issues concerning the reliability of the information contained
in academic journal articles should be dealt with at source, for
example by strengthening the peer review process as recommended
in our 2011 Report, rather than by effectively bypassing academic
publication through greater reliance on CSRs. We therefore do
not support any move to make it mandatory for non-commercial trials
to produce a CSR, or any other document of an equivalent level
of detail. However, we recognise that CSRs can provide a useful
contribution to the scientific literature and, once a regulatory
decision has been reached, we see no compelling reason why CSRs
should not be placed in the public domain, with identifiable patient
data redacted. (Paragraph 79)
Level 4: Individual patient-level data
19. We
are not in favour of placing anonymised individual patient-level
data (IPD) in the public domain in an unrestricted manner, as
we consider that the risk to patient confidentiality is too great
and, for many past and current trials, this level of disclosure
would go beyond the confines of previously obtained patient consent.
Nevertheless, we recognise the scientific value of IPD and consider
these data to be currently underutilised. We agree with the Caldicott
2 Review that providing specific individuals with controlled access
to personal confidential data such as IPD through carefully managed
and secure "safe havens", together with contractual
agreements about how that data can be used, is the best way forward.
We also consider that access should be facilitated by an independent
"gatekeeper", responsible for evaluating research proposals
and ensuring that data is handled responsibly and in a way that
makes a useful contribution to scientific knowledge. (Paragraph
88)
20. The UK could take
the lead in shaping how a global system for sharing IPD for non-commercial
trials might operate and a national system covering all non-commercial
UK trials would be capable of delivering potentially significant
benefits. We consider that the Health Research Authority (HRA)
could act as developer, administrator and gatekeeper for a central
repository of IPD for non-commercial UK trials. In order to achieve
this, template consent forms provided by the HRA should allow
for and emphasise to trial participants the benefits of data sharing.
Research Ethics Committees should also take into account any transparency
restrictions imposed by patient consent forms when evaluating
research proposals for clinical trials. (Paragraph 89)
Past initiatives to increase clinical trial transparency
21. We
support the development of the EU Clinical Trials Register (EU
CTR) and hope it will also include summary-level results, as promised,
by the end of 2013. However, we do not consider the register to
represent a complete solution to the problem of non-registration
of clinical trials, as it does not include all the trials that
have been conducted on all medicines currently available in Europe.
The Government should encourage the EMA to further increase the
scope of the EU CTR, for example by including phase I trials and
trials conducted outside of the EU. We also recommend that the
Government monitor the EMA's fulfilment of its pledge to include
trial results on the register and obtain an explanation if the
EMA fails to do so by the end of 2013. (Paragraph 94)
22. As a major direct
and indirect funder of clinical trials, the Government can influence
behaviour across both the public and charitable sectors. This
influence has not been wielded effectively to increase transparency,
meaning that many publicly-funded trials remain unregistered and
unpublished. We recommend that registration in a WHO-listed registry
and publication of summary-level results in a peer-reviewed journal
be made contractual requirements for all publicly-funded trials,
including research supported by the Charity Research Support Fund.
The wording of these requirements should be standardised across
all contracts to ensure consistency. We also recommend that public
funders of research rapidly put in place mechanisms to monitor
compliance with transparency policies and ask the Government to
detail in its response to this Report how and when this will be
done. (Paragraph 99)
23. Since the Government
has encouraged industry to disclose retrospectively the results
of past trials, we think that it should be prepared to do the
same for the major trials that it has funded. We therefore recommend
a retrospective audit of all public phase III trial grants awarded
since 2000, followed by action to ensure that any failures to
register or publish the summary-level results of these trials
are rectified within 12 months. Any failures to correct these
mistakes should be taken into account when considering future
grant applications from principal investigators of previously
unregistered or unpublished trials. In future, for grants awarded
to fund phase III clinical trials we suggest that the MRC and
the NIHR allocate a small proportion of funding to cover the time
and resource requirements of preparing a manuscript for publication,
and withhold this funding until the results of the trial are ready
to be published. (Paragraph 100)
24. We suggest that
the academic publishing industry put in place robust measures
to ensure that unregistered trials are not just rejected, but
that the trial sponsor(s) and funder(s) are notified that the
trial has not been properly registered. (Paragraph 101)
Current initiatives to increase clinical trial
transparency
25. In
mandating trial registration, publication of summary-level results
and publication of CSRs for commercial trials, we consider that
the European Parliament's ENVI Committee appears to have reached
a reasonable decision regarding the transparency requirements
of the proposed EU Clinical Trials Regulation. (Paragraph 104)
26. The Government
should clarify why Department of Health or MHRA officials were
not present at recent discussions relating to the EMA's revised
transparency policy. We hope that the Government will be more
fully engaged in the next stages of the development of this policy.
(Paragraph 106)
27. We agree with
the Joint Committee that the Care and Support Bill should make
the promotion of research transparency a statutory objective of
the HRA and we recommend that the Government includes the necessary
provision. (Paragraph 109)
28. Research Ethics
Committees should have a role in considering and monitoring compliance
with transparency policies. As such, we welcome the HRA's new
transparency policy and support, in principle, the proposals made
in its May 2013 paper. We recommend that the HRA initially retains
full responsibility for policing its own policies and ensures
that all trials have been registered and published according to
an agreed timeline, rather than performing checks on a sample
basis. In addition, there must be penalties for non-compliance.
We recommend that the HRA provides us with a progress update on
implementation of its new transparency policy by the end of 2013.
(Paragraph 110)
29. We recognise the
efforts of some members of the pharmaceutical industry, particularly
GSK, to increase clinical trial transparency and hope that other
companies will act in the same spirit in implementing industry-wide
principles for responsible clinical trial data sharing. We suggest
that all companies endorsing such principles agree and report
on a common set of clinical trial transparency metrics each year
in their annual reports. (Paragraph 113)
30. We are supportive
of the broad aims of the AllTrials campaign and agree that all
clinical trials should be registered and their results reported.
We suggest that the AllTrials campaign clearly set out what it
considers a full trial report to contain, particularly when prepared
for non-commercial purposes, so that its supporters can work together
to achieve a specific set of common goals. (Paragraph 116)
Value-based pricing and the renegotiation of the
PPRS
31. Value-based
pricing (VBP) is predicated on the idea that the Government is
able to influence industry's behaviour through its spending power.
We therefore consider VBP—and to a lesser extent the PPRS—to
be tools that could also be used to encourage and reward industry
for making its clinical trial data more transparent. The Government
should consider ways in which clinical trial transparency could
be incentivised in the future through VBP and the current renegotiation
of the Pharmaceutical Price Regulation Scheme (PPRS). (Paragraph
118)
Incorporating emerging evidence into clinical
practice
32. Increased
transparency is unlikely to lead to improved medical outcomes
unless mechanisms are in place to ensure that emerging evidence
is quickly and effectively incorporated into clinical practice.
Given the high degree of reliance placed on NICE's guidance by
health professionals, we consider it essential that this advice
remains fully up to date and that processes are in place to ensure
that emerging evidence is rapidly incorporated. The Government
should ensure that, as improved transparency leads to ever greater
volumes of trial data becoming available, NICE continues to receive
the resources it needs to assimilate emerging evidence into its
guidance in a timely manner. (Paragraph 122)
Conclusions
33. We
consider that more can and should be done to make the UK a more
attractive location to conduct clinical trials. (Paragraph 123)
34. We are confident
that the Government is aware of these problems and the need to
resolve them, but its promises have yet to be matched by effective
action. We strongly urge the Government to act on our recommendations
and put an end to these long-standing issues, so that the UK can
continue to make progress towards being the location of choice
for the global life sciences industry. (Paragraph 124)
35. We call on the
Government to take decisive steps, as outlined in this Report,
to ensure greater transparency in all future trials conducted
in the UK, in order to demonstrate to the rest of the world how
effective solutions might one day be applied at a global level.
(Paragraph 125)
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