"Drug companies accused of holding back complete information on clinical trials," The Guardian reports.
MPs have just published a report expressing concern that drug companies are withholding evidence about how effective drugs such as Tamiflu actually are.
The report, from the House of Common Public Accounts Committee, says it heard evidence that clinical trials of medicines that have a favourable result are about twice as likely to be published as those giving unfavourable results.
This has been a long-recognised issue in evidence-based medicine and is known as publication bias.
Though despite efforts by both researchers and regulators to overcome publication bias, many commentators maintain it is an ongoing problem.
It says that in the last few years the government spent £424 million on stockpiling Tamiflu in case of a flu pandemic. However, there is little agreement as to how effective the drug is, particularly in preventing complications and deaths from flu.
Discussions on the issue, it says, have been hampered because not all the information from clinical trials on Tamiflu have been made available.
The report also voices concern as to whether the National Institute for Health and Care Excellence (NICE), which advises on the use of drugs in the NHS, has appropriate access to all the information made available to the regulatory bodies as part of the licensing process.
The report calls for greater transparency and recommends that all clinical trials, whether published or unpublished, should be made available for wider scrutiny.
Who produced the report?
The report comes from the Committee of Public Accounts, a parliamentary committee comprising members from all the major political parties. The Committee’s role is to examine how effectively and efficiently public money is spent, focusing in particular on value for money criteria.
Before producing a report it takes evidence from relevant sources and experts.
In this report evidence was taken from:
- Dr Ben Goldacre – a researcher in epidemiology and a campaigner for greater transparency
- Dr Fioan Godlee – Editor in Chief of the British Medical Journal
- Una O’Brien – Permanent Secretary of the Department of Health
- Sir Andrew Dillion – Chief Executive of the National Institute for Health and Care Excellence (NICE)
- Professor Sir Kent Woods – Chief Executive of the Medicines and Healthcare Products Regulatory Agency (MHRA)
- Professor Dame Sally Davies – the Chief Medical Officer for the Department of Health
Written evidence was also taken from:
- Roche, the manufacturers of Tamiflu
- the Cochrane Collaboration, an independent non-proft body that carries out systematic reviews on the evidence for specific treatments
What does the new report say?
The latest report from the Committee covers several related areas:
- The availability of clinical trial results
- How the agencies involved in licensing and approving medicines share information
- The stockpiling of Tamiflu
The Committee points out that 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 Committee says it 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”.
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, it argues. This undermines the ability of doctors, researchers and patients to make informed decisions about which treatment is best.
The problem of non-publication of clinical trial results has been known since the mid-1980s, say the MPs, 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.
The Committee also heard evidence that trials with positive results are about twice as likely to be published as trials with negative results.
It also says that none of the latest proposals from regulators or industry adequately address the issue of access to the results of trials from previous years on the medicines in use today.
The role of NICE and the MHRA
The report also comments on the role of NICE, the body that provides evidence-based guidance to health professionals on treatments; and on the Medicines Healthcare and Regulatory Products Agency (MHRA), the government body responsible for regulating and licensing all medicines.
It says that that NICE and the MHRA do not routinely share information provided by manufacturers during the process for licensing medicines. It explains that when applying for a license for a drug, 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.
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.
The stockpiling of Tamiflu
The report points out that between 2006-07 and 2012-13, the Department of Health spent £560 million on stockpiling two antiviral medicines for use in a flu pandemic – £424 million on Tamiflu (oseltamivir) and £136 million on the other antiviral used to treat flu, Relenza (zanamivir).
Yet it says there remains a lack of consensus over how well Tamiflu works. There also disagreement about whether medicine 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; yet according to the Cochrane Collaboration, (the independent body that publishes systematic reviews of the evidence on treatments) this was not the case.
It wrote to the Committee to draw attention to trials where the Cochrane Collaboration concluded the European regulators had incomplete information. “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 concludes.
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.”
It says the Cochrane Collaboration is now receiving full clinical study reports from Roche, the manufacturer of Tamiflu. This will enable it to complete its review of the effectiveness of Tamiflu with complete information for the first time.
It concludes: “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.”
It also points out that The Department of Health 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 flu pandemic. During the swine flu 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 of Health has put in place additional guidance for the storage of antivirals following distribution during a pandemic.
The case for stockpiling antiviral medicines at the current levels is based, it says,” on judgement rather than evidence of their effectiveness during an flu pandemic".
It says that despite there being only limited evidence the business case developed by the Department of Health assumed Tamiflu would give 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.
What does the report recommend?
The report makes several key recommendations which include:
- The Department of Health it says 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.
- The Department and the MHRA should ensure, both prospectively and retrospectively, that clinical trials, including methods and results, are registered on an appropriate registry that is available for wider independent scrutiny.
- NICE should ensure that it obtains full methods and results on all trials for all treatments that it reviews 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.
- Once the Cochrane Collaboration has completed its review of Tamiflu using all clinical study report information, further consideration is required into whether it is necessary to revisit previous judgments about the efficacy of Tamiflu.
What does the drug industry say?
In a response to the report, Bina Rawal, the medical and innovation director of The Association of the British Pharmaceutical Industry (ABPI), which represents drug manufacturers in the UK, said:
"It is misleading to suggest that the pharmaceutical industry routinely withholds clinical trial data from doctors and researchers.
“In late 2013, an ABPI-commissioned study was published in a peer-reviewed journal. This study highlighted a positive trend of increasing levels of disclosure for industry-sponsored clinical trials, with almost nine out of 10 of all industry-sponsored clinical trials disclosed by January 31 2013. The research covers new medicines approved between 2009 and 2011, which includes trials conducted over the preceding 10 or more years – i.e. during the entire development programme.
“However we recognise that there is still work to be done and we are continuing on a journey to achieving greater clinical trial transparency. The ABPI has made available a new clinical trial disclosure toolkit to assist companies and will continue to engage with key stakeholders on this issue.”
So Tamiflu doesn’t work?
As the Committee points out, not enough evidence has been made publically available to know how well Tamiflu works. The Cochrane Collaboration’s systematic review into the effectiveness of Tamiflu in preventing and treating flu in adults and children – published in January last year – said it was incomplete because of difficulties obtaining sufficiently detailed information from the manufacturer (Roche).
Overall, the review included 25 studies, but had to exclude 42 relevant studies due to the lack of patient information or unresolved problems in the data.
While a review of Relenza undertaken at the same time was postponed due to new information about how the drug affected individual patients being made available by the manufacturer (GlaxoSmithKline).
As the Committee says, the debate on whether Tamiflu is effective continues. The simplest way to resolve it would be to allow independent reviewers to access the full existing results of studies into it.
As with most things in medicine, prevention is better than the cure. If you are in a vulnerable group known to be more at risk for complications from flu then you should ensure your flu vaccinations are up to date.
Read more about who should get the flu vaccine.