Conclusions and recommendations
On clinical trials
1. We
were surprised and concerned to discover that information is routinely
withheld from doctors and researchers about the methods and results
of clinical trials on treatments currently prescribed in the United
Kingdom. This problem has been noted for many years in the professional
academic literature, with many promises given, but without adequate
action being taken by government, industry or professional bodies.
This now presents a serious problem because the medicines in use
today came on to the market—and were therefore researched—over
the preceding decades. None of the latest proposals from regulators
or industry adequately addresses the issue of access to the results
of trials from previous years on the medicines in use today.
Recommendation: The Department should take
action to ensure that the full methods and results are available
to doctors and researchers for all trials on all uses of all treatments
currently being prescribed, and should also ensure that there
is clear and frequent audit of how much information is available
and how much has been withheld.
2. The
results of clinical trials on humans are the key evidence used
by regulators, researchers and clinicians to assess whether a
medicine works and how safe it is. Medicine manufacturers submit
evidence on products they wish to market in the UK to the Medicines
and Healthcare Products Regulatory Agency (MHRA) or the European
Medicines Agency (EMA).
3. The
scope for independent scrutiny of a medicine's effectiveness is
undermined by the fact that the full methods and results of many
clinical trials are not made available to doctors and researchers.
The problem of non-publication of clinical trial results has been
known since the mid-1980s. We also heard evidence that trials
with positive results are about twice as likely to be published
as trials with negative results. While several clinical trial
registries have been established, none covers all clinical trials
on all uses of all treatments currently being prescribed worldwide.
There have been recent announcements by the EMA, and some manufacturers,
to improve access to information about clinical trials but none
adequately addresses the issue of incomplete disclosure throughout
medicine. Opening up information about all clinical trials to
medical researchers would support the work of regulators by permitting
thorough, independent external review by doctors and researchers
.
Recommendation: The Department and the MHRA
should ensure, both prospectively and retrospectively, that clinical
trials are registered on an appropriate registry and that the
full methods and results of all trials should be available for
wider independent scrutiny, beyond the work undertaken by regulators
during the licensing process.
4. NICE
and the MHRA do not routinely share information provided by manufacturers
during the process for licensing medicines. When
applying for a licence, manufacturers have a legal obligation
to provide all the information on the safety and efficacy of a
medicine that is required by European regulators. However, NICE
does not have statutory powers to demand information from manufacturers,
in contrast to the Institute for Quality and Efficiency in Healthcare
in Germany, which performs a similar role to NICE. NICE seeks
confirmation from the medicine manufacturer's UK medical director
on the completeness of information, but this may not include all
clinical trials in other parts of the world, not least because
UK medical directors may themselves not have full information.
The MHRA confirmed there was no legal obstacle that would prevent
it from sharing information with NICE. However, there is no routine
sharing of the information provided by manufacturers to regulators
as part of the licensing process with NICE. This leads to the
risk of omissions and duplication in the collection of evidence.
Recommendation: NICE should ensure that
it obtains full methods and results on all trials for all treatments
which it reviews, including clinical study reports where necessary;
make all this information available to the medical and academic
community for independent scrutiny; and routinely audit the completeness
of this information. NICE and the MHRA should put in place a formal
information-sharing agreement to ensure when NICE appraises medicines
it has access to all of the information provided to regulators
by the manufacturer during the licensing process.
On Tamiflu
5. The
number one risk on the Government's national risk-assessment for
civil emergencies, ahead of both coastal flooding and a major
terrorist incident, is the risk of pandemic influenza. Between
2006-07 and 2012-13, the Department spent £560 million on
stockpiling two antiviral medicines for use in an influenza pandemic—£424
million on Tamiflu and £136 million on Relenza.
6. There
remains a lack of consensus over how well Tamiflu works and there
is disagreement about whether regulators and NICE received all
the information on Tamiflu during the licensing process. The
MHRA is confident that European regulators received all the information
on Tamiflu. However, following the hearing the Cochrane Collaboration[1]
wrote to the Committee to draw attention to trials where the Cochrane
Collaboration concluded the EMA had incomplete information. Table
1 of Cochrane's submission sets out the information that the Cochrane
Collaboration received from the EMA in response to a request for
all information held by the agency, and it is plain that for many
large trials no information was available, and that for many more
trials only partial information was available. The Committee shares
the concern expressed by the Cochrane Collaboration when it wrote:
"We find it perplexing that the regulators continue to state
that they had all the available evidence". The Cochrane Collaboration
is now receiving full clinical study reports from Roche, the manufacturer
of Tamiflu, which will enable the Cochrane Collaboration to complete
its review of the effectiveness of Tamiflu with complete information
for the first time. Whether or not the Cochrane Collaboration's
overall recommendation changes, it is extremely concerning that
there has been a five-year delay and that there continues to be
a lack of clarity over who saw what.[2]
Recommendation: Once the Cochrane Collaboration
has completed its review of Tamiflu using all clinical study report
information, the Department, MHRA and NICE should consider whether
it is necessary to revisit previous judgements about the efficacy
of Tamiflu.
7. The
case for stockpiling antiviral medicines at the current levels
is based on judgement rather than evidence of their effectiveness
during an influenza pandemic. It is difficult to extrapolate the
results of clinical trials involving seasonal influenza to Tamiflu's
effectiveness during a pandemic. During 2008, the Department developed
a business case to establish a stockpile of antivirals and pre-influenza
pandemic vaccine. The business case included increasing antiviral
medicines to 80% population coverage in a two-stage process. Despite
there being only limited evidence and widespread disagreement
among regulators and other bodies internationally on whether Tamiflu
confers any benefits on complications and mortality, the business
case used an assumption that there would be a 40% to 50% reduction
in complications and mortality. This assumption was based on advice
from a range of experts including the Department's Scientific
Pandemic Influenza Advisory Committee.
Recommendation: Before spending the £49
million to maintain a stockpile at 50% population coverage, scheduled
for 2013-14, the Department should review the appropriate level
of population coverage; the level of stockpiling in other countries;
and take into consideration the fact that the patent for Tamiflu
expires in 2016.
8. The
Department wrote off £74 million of Tamiflu as a result of
poor record-keeping by the NHS on how the medicine had been stored
during the 2009 influenza pandemic. During the pandemic, Tamiflu
was distributed to many places around the country. When unused
stocks were returned, it was not clear whether they had been stored,
as required, below 25C. The Department has put in place
additional guidance for the storage of antivirals following distribution
during a pandemic.
Recommendation: The Department should seek
assurances that bodies involved in the distribution of antiviral
medicines during a pandemic follow the Department's revised guidance
and have robust storage and quality-control systems in place.
1 The Cochrane Collaboration is an international network
that undertakes systematic reviews of primary research in healthcare
and health policy. Back
2
Cochrane Collaboration (June 2012), Response to oral evidence
taken before the Public Accounts Committee: Clinical Trials -
Tamiflu. Back
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