more drug company shenanigans: nonpublication of clinical trials

as part of the safeguard for clinical trials, the FDA modernization act mandated establishment of the Registry of Clinical Trials, with public access to information.  in 2007 the FDA Amendments Act expanded it to include prior studies, posting almost all trials at clinicaltrials.gov (by law: posting all prospective clinical study of health outcomes, studies involving drugs or other products regulated by the FDA, and controlled intervention studies in humans). Failure to comply with this mandate could result in penalties of up to $10,000 per day and withholding of funds from investigators sponsored by the NIH.

In a recent studies reported in BMJ (see clinical trials negative results bmj 2013 in dropbox or doi: 10.1136/bmj.f6104) investigators looked at all trials with at least 500 participants in the clinical trials registry and completed prior to January 2009 and published by November 1, 2012. (These researchers focused on large studies because these would most likely be published if presented to a medical journal and therefore if not published, more likely represented a conscious decision not to pursue publication).  they found 585 registered trials, of which 29% (171 studies) remained unpublished.  300,000 people were enrolled in these 171 studies. Of these 171 trials that remained unpublished, 38 did have results available on clinical trials.gov. But 133 had no results available either in published form or in clinicaltrials.gov. (one could argue that even if these results were available at that website, there was an obligation to publish the data from these large trials in a peer-reviewed journal). They also found that non-publication was more common among trials that received industry funding (32%) than those that did not (18%).

The indications of the above are quite profound.  As I mentioned in prior emails, there has been a dramatic shift in this country in funding of research.  Ronald Reagan as president effectively privatized much of healthcare research.  Prior to Reagan, articles in medical journals were predominantly sponsored by the government (NIH, NSF).  However,over the past several decades the vast majority of research has been sponsored by the private sector (almost all studies in the best peer-reviewed medical journals are drug or medical device company sponsored), with the inherent conflict of interest in presenting negative results for drugs/medical devices they want to promote. There has been public exposure of some of the flagrant examples, such as publishing only a smaller positive study on gabapentin for neuropathic pain and suppressing a much larger study which found a negative results. This article reveals that the safeguards that the FDA had placed to protect the public have been frequently ignored.

I will also cut and paste a relevant recent article in NY Times  ("Doctors Say Heart Drug Raised Risk of an Attack" by Andrew Pollack, 11/19/2013):

Cardiologists have accused a small drug company of withholding data from a clinical trial showing that the company’s drug, meant to reduce the risk of heart attacks, increased the risk instead.

The cardiologists said that the company, Anthera Pharmaceuticals, did not turn over data to academic investigators, as it was required to do, for more than a year.

“Despite a contract that required transfer to the academic authors, the company stonewalled every attempt to acquire the data,” Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, said in an email on Tuesday.

Studies and lawsuits have shown that many clinical trial results, particularly negative ones, are not published. Critics say that hampers medical practice and violates an obligation to patients, who try experimental treatments in part to advance knowledge.

“We think that when you enter into a clinical trial, and we enter into contracts with our patients, there’s an obligation that we are going to do the right thing,” said Dr. Nicholls, a cardiologist at the South Australian Health and Medical Research Institute in Adelaide.

The Phase 3 trial involved 5,145 patients in various countries with acute coronary syndrome, a sudden blockage of blood flow to heart muscles. It tested whether the drug varespladib could reduce the risk of heart attacks, stroke, death and chest pains requiring hospitalization.

The trial was terminated early by the safety monitoring committee in March 2012. The company announced that the committee had determined that there was no chance the drug would succeed in the trial.

The results show that patients who got the drug actually had a higher risk of cardiovascular problems, mainly heart attacks, than those who received a placebo.

Dr. Nicholls said in an interview that Anthera continually promised to provide the complete data but did not. Finally, the company told him this spring that it had given the drug back to Eli Lilly, the original developer of the drug. The investigators were then able to get the data almost immediately from Lilly, he said.

Dr. Nicholls said that Anthera was also supposed to ensure that all patients were surveyed six months after the trial ended to see if they were still alive. But that data was collected for only 31 percent of the patients, making it impossible to clearly determine if the drug had increased the risk of death, he said.

so, this all strongly suggests that we as clinicians be very careful about being early-adopters to new medications or medical devices, since the studies are largely supported by drug/medical device companies, and we cannot be certain about the accuracy or completeness of the data we see. and to make matters worse, the FDA (under pressure from drug companies) has been releasing drugs earlier than before with the expectation of post-marketing surveillance...