Richard Bacon MP, member of the Committee of Public Accounts, said:
“The full results of clinical trials are being routinely and legally withheld from doctors and researchers by the manufacturers of medicines.
“This has ramifications for the whole of medicine. The ability of doctors, researchers and patients to make informed decisions about treatments is being undermined. Regulators and the industry have recently made proposals to open up access, but these do not cover the issue of access to the results of trials in the past which bear on the efficacy and safety of medicines in use today.
“Research suggests that the probability of completed trials being published is roughly 50 per cent. And trials which gave a favourable verdict are about twice as likely to be published as trials giving unfavourable results.
”This is of extreme concern to this Committee. The Department and MHRA must make sure, both prospectively and retrospectively, that clinical trials are registered and the full methods and results of all trials are available for independent wider scrutiny by doctors and researchers.
“There is also no routine sharing between NICE and the MHRA of information provided by manufacturers during the process of licensing medicines.
“There is still a lack of consensus over how well the antiviral medicine Tamiflu, stockpiled for use in an influenza pandemic, actually works. The lack of transparency of clinical trial information on this drug to the wider research community is preventing proper discussion of this issue among professionals. We are disturbed by claims that regulators do not have access to all the available information.
“The case for stockpiling antiviral medicines at the current level is based on judgement rather than on evidence of their effectiveness during an influenza pandemic. Before spending money in future to maintain the stockpile the Department needs to review what level of coverage is appropriate. It should look at the level of stockpiling in other countries, bearing in mind that the patent for the medicine runs out in 2016.”
Richard Bacon was speaking as the Committee published its 35th report of this Session which examined the availability of clinical trial results; how the Medicines and Healthcare Products Regulatory Agency (MHRA) and the National Institute for Health and Care Excellence (NICE) share information; and the stockpiling of Tamiflu.
The Committee took evidence from the Department of Health, the MHRA, NICE, Dr Ben Goldacre and Dr Fiona Godlee, Editor-in-Chief of the British Medical Journal.
The Committee was 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.
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.
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).
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. The Committee 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.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.