One of the key issues to emerge from the recent spat between Sir Rory Collins and the BMJ about statins (1) has been the refusal of the Cholesterol Treatments Trialists’ Collaboration (CTT) at Oxford University to allow open access to the original clinical trial data. The independent panel set up by the editor of the BMJ concluded that it:
“strongly believes that the current debates on the appropriate use of statins would be
elevated and usefully informed by making available the individual patient-level data
that underpin the relevant studies” (2).
There have been suggestions that the information which is released for publication and to the regulatory bodies is not a true representation of the primary data obtained in the clinical trials (3).
Recently the original data on ‘flu vaccines have been released and it is especially pertinent to discover the insight this example provides.
Tamiflu is one of the medicines used to treat or prevent many different types of flu including bird flu and swine flu. It is recommended by the World health Organisation (WHO) and has been approved by the Food and Drugs Administration (FDA) in the US and by the European Medicines Agency (EMA). In the UK the government has spent £424m in recent years but much of this has had to be discarded because it was never used according to a critical report by the National Audit Office (4).
It is claimed that it will reduce the duration and severity of the flu but questions have been raised about the evidence on which this is based.
The House of Commons Select Committee on Science and Technology has been conducting an Inquiry into “Clinical Trials and Disclosure of Data”. In particular the inquiry focused on the need for transparency of the results of clinical trials, which are primarily concerned with the evaluation of drugs prior to approval (5).
Specific information relating to Tamiflu was presented in a submission from the Cochrane Collaboration which is an international network of volunteer scientists who carry out reviews of evidence on interventions in health care using highly structured and reproducible methods. Cochrane reviews are considered as the gold standard in evidence-based decision making for interventions and are used by many governments in the formulation of public health policies. It is independent of the pharmaceutical companies and any other potential conflicting interests. A group of their researchers had been reviewing 2 vaccines used for ‘flu, namely zanamivir (Relenza, GW now GSK) and oseltamir (Tamiflu, Roche). In their submission they explained the problems encountered in their attempts to obtain the information which was required for their evaluations. In 2009 the team was doing an update of an earlier review which had been published in 2005, when it received a query from a Japanese paediatrician. Dr Keiji Hayashi wanted to know how it was possible that in our 2005 update we had included 8 unpublished Tamiflu trials contained in extreme summary form within another review funded by Roche and carried out by Roche staff and consultants. How could we possibly have done that as we had not seen the original studies? As a consequence Roche was approached but only agreed to release the original raw data if the reviewers would sign a confidentiality clause. Obviously this was not possible because it would compromise the independence, transparency and reproducibility of the report. However as result of coverage on Channel 4 News and in the British Medical Journal Roche publicly promised full study reports. Despite only 4-5 parts of the 10 trials were handed over as Roche claimed that would all that was needed. Subsequently the documents were released and much to their surprise the researchers discovered that there is a clinical study report for each drug trial conducted. This is a complex document containing hundreds or thousands of pages of information with minute details about trials, their planning and execution. Up to that point the Cochrane reviewers were totally dependent on a journal article of a few pages.
At the outset they were aware of 26 trials but it subsequently emerged that there were 123 trials on Tamiflu. The fact that so many were kept under wraps may have had damaging effects on public and clinician confidence in the rigour of how medications are assessed in the UK for safety and effectiveness. There is also a risk that NHS funds have not been used for interventions which offer the best value for money.
- Nevertheless the Cochrane team did succeed in gaining access to the material which Roche had submitted to the EMA as well as comments made by the FDA on Tamiflu. As a result the team was able to compare the more detailed information with relatively few publications which had been available previously. They found that there were discrepancies in reporting harms and some important aspects of study design between publications and regulatory reports. There were also suggestions that the drug interferes with the natural antibody production. If this is the case it would mean that the use of Tamiflu weakens natural host defences and may weaken response to any antigen stimulating interventions such as vaccines. The regulatory evidence released from EMA and FDA indicates that the positive effects of the drug are not as marked as those claimed by the manufacturer and its consultants in industry-sponsored publications. In agreement with the FDA there was no reliable evidence to conclude that Tamiflu is effective against influenza complications (e.g. pneumonia) and person-to-person transmission.
In the light of the evidence which has come to light the authors question whether the government would have agreed to stockpile Tamiflu if the complete picture was available when the decision was made. They also note that the WHO and the Centers for Disease Control (CDC) in the US apparently disregard this information and continue to recommend Tamiflu.
This particular case study is confirmation that information has been manipulated by one company in order to improve the chances of approval being granted by the regulatory authorities. There is also no doubt that this type of action is used to advantage in the market place.
Clearly this revelation has major implications for statins. It would not be in the least surprising that a similar approach is being used by the manufacturers of statins. It would certainly explain why Rory Collins and his colleagues at the CTT are so reluctant to allow any outsiders to have access to the clinical trial data which they have. There are already serious doubts about the value of statins, especially when used as a preventive measure in people who have not had problems with heart disease (6). The Department of Health and other bodies such as NICE must insist that the statin data at the CTT and elsewhere is open to scrutiny as a matter of urgency.
NOTE: It is extremely unfortunate that the Cochrane team which recently review statins did not show anything like the same determination as the one investigating Tamiflu. Had it done so it might well have reached a conclusion which was much less favourably disposed towards the use of statins (7). It is rather ironic that relied so heavily on the information provided by the CTT and apparently did not have access to the original trial data. As a consequence, the reputation of the Cochrane Collaboration has become somewhat tarnished, which is a great pity!