As international clinical trials day approaches (20th May) I’ll be posting a series of articles on AllTrials.
Here is part of my response to the Science and Technology Committee plan to examine the regulation of clinical trials on behalf of the Centre for Evidence-Based Medicine
The evidence for harms for witholding clinical trial data
Whilst modern medicine delivers great benefits to society, its harms due to the withholding of data often prove devastating—with numerous incidents, ranging from thalidomide and antiarrhythmic drugs to Cox II inhibitors. Work from several investigators have highlighted the problems associated with withheld data in which poor regulatory practices have led to direct patient harm, excess costs and delays in the delivery of effective treatments.
Firstly, the extent of underreporting should not be underestimate. A study of 546 drug trials, published between 2000 and 2006 reported only 2/3rds had published their results. Rates of trial publication within 24 months of study completion ranged from 32% among industry-funded trials, to 56% among non-profit or non-federal organization–funded trials.
A further analysis of trials listed on Clinical Trials.Gov, found that of 677 trials completed by 2007 only 46% were published in a peer reviewed biomedical journal, indexed by Medline, within 30 months of trial completion.
Mandatory reporting of trials appears to have made little difference. For example, the overall rate of compliance with the mandatory reporting rate for 2009 trials listed on Clinical Trials.gov within one year following completion, is only 22%. A further study of clinical trials.gov data between 2009 and 2010 reported that only 52% of 152 trials had associated publications within 2 years after posting.
Secondly, Six recent case studies are outlined which highlight the problem and the harm caused: (more cases studies can be provided upon request)
Rofecoxib: failure to disclose evidence of harm.
Research by Psaty et al published in JAMA is an example of the importance of withheld data. This case study, by reviewing information provided by the FDA, demonstrated two pivotal published articles of rofecoxib did not include analyses of mortality data, and because of this the studies concluded rofecoxib is “well tolerated.”
In direct contrast, and at the same time as publication, the company’s internal intention-to-treat analyses of pooled data from the same trials identified a significant increase in total mortality. This equated to an overall mortality of 34 deaths among 1069 rofecoxib patients and 12 deaths among 1078 placebo patients (HR, 2.99; 95% CI, 1.55-5.77).
What is striking about this case is these mortality analyses were neither provided to the US FDA nor made public.
Of more concern was the data submitted to the FDA in a Safety Update Report in July 2001. This data, submitted by the sponsor, used on-treatment analysis methods and reported 29 deaths (2.7%) among 1067 rofecoxib patients and 17 deaths (1.6%) among 1075 placebo patients, thus masking the true mortality difference.
Rosiglitazone: research misconduct and failure to disclose harms
Rosiglitazone is a thiazolidinedione class of drug which was marketed as an addition and/or stand-alone drug to the oral hypoglycaemic agents available to treat patients with uncontrolled type 2 DM. Annual sales peaked at approximately $2.5bn in 2006; the drug is now withdrawn due to safety issues.
Internal GSK company emails reveal a submitted journal publication, which showed rosiglitazone increased the risk of myocardial infarction, was leaked to GSK. GSKs internal analysis and their company statisticians confirmed the findings and internal company emails demonstrated the company had already come to similar conclusions.
Oseltamivir: Lack of access to full trial programmes
Further to these investigations we have taken a similar approach to Psaty in the analysis of the effects of oseltamivir.  Only in response to substantial publicity generated by a joint BMJ-Channel 4 News investigation of oseltamivir, did Roche publicly pledge to make its unpublished full clinical study reports available.  The subsequent work has gone on to find a high risk of publication and reporting bias in the trial programme of oseltamivir, which significantly undermines the results published in journals.
Paroxetine: withholding trial data and risk of suicide
GSK was caught withholding clinical trial data showing Paroxetine increased the risk of suicide in young people. The Chief Executive of the MHRA said, “I remain concerned that GSK could and should have reported this information earlier than they did.
Reboxetine: effects of publication bias
Reboxetine was eventually found to be an ineffective and potentially harmful antidepressant after researchers found that 74% of the data from clinical trials had been suppressed during the lead up to the approval of the drug for the acute treatment of severe depression.
Rimonabant 2007: withholding data and delays in withdrawal
In the FDA’s concluded the French manufacturer Sanofi-Aventis failed to demonstrate safety of rimonabant and did not recommend the anti-obesity treatment. The drug had been on sale in Europe for the year previously – The company spent nearly four years withholding data on the risks and benefits of two weight-loss drugs. Acomplia – had to be taken off the market: its harms outweighed its benefits.
There are many more examples that I am sure readers can highlight.