Company-funded postmarketing trials not improving drug safety surveillance: study

A recent study published in The BMJ found that phase 4 trials funded by the industry are not effective in identifying safety issues.

Conflicts of interest might not be avoidable in clinical trials since so many of them are sponsored by the biopharma companies actually making them. One would expect them to double their efforts when drug safety is at stake, but a recent study by German researchers found that postmarketing trials funded by the industry are not effective in identifying safety issues.

That conclusion was made in a study published in The BMJ after researchers examined 558 such studies mainly conducted in Germany spanning a three-year period between 2008 to 2010, and found that not a single adverse event was reported to regulatory authorities.

Those studies recruited an average of 2331 patients (or a median of 600) and 270 physicians (or a median of 63) for each. Doctors were paid €441 on average (€200 median) per patient, and €19,424 on average (€2,000 median) for one trial, the study found.

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Only a third of phase 4 trials were examining drugs approved less than two years before the trials’ commencement, and in those studies, remuneration for physicians was averagely speaking twice as much as those in other trials, the study found.

“Sample sizes are generally too small to allow the detection of rare adverse drug reactions, and many participating physicians are strictly obliged to maintain confidentiality towards the sponsor,” the researchers write in the study’s conclusions. And they only found five of all 558 postmarketing studies’ results in scientific journals.

Moreover, that doctor-patient ratio can have lower data quality because training and monitoring so many physicians is quite cumbersome and inefficient, said Angela Spelsberg, M.D., an epidemiologist at Comprehensive Cancer Center Aachen and the lead author of the study, as reported by Reuters. Yet, researchers also pointed out the actual number of participating physicians could be smaller as doctors often work on several studies at the same time.

Postmarketing trials, also known as phase 4 trials, are conducted after the approval and marketing of a new drug to evaluate its long-term effects—including efficacy and rare side effects—more thoroughly in larger populations.

The U.S. FDA only requires some postmarketing trials when, for example, there’s a known serious risk of a drug product, or the company is trying to expand the product’s usage for children; while others are the drugmakers’ prerogative.

For all trial stages before an approval, the sum of participants enrolled sometimes stay around a thousand, and rarely exceed 3,000, and that also include those who received placebo instead of the drug candidate under investigation.

That kind of sizes, though enough for detecting common adverse events, are not sufficient for rare or very rare side effects, as defined by the Council for International Organizations of Medical Sciences and also widely recognized as those with 1 in 1,000 to 1 in 10,000 occurrence rates. That’s why regulators and healthcare professionals expect phase 4 trials, which have longer time spans and hence the capability to enroll large numbers of patients, to identify those rare events.

According to the most recent edition of an annual report prepared by the agency, as of Sep. 30, 2015, all together 856 applications were undergoing postmarketing trials, and 575 applications should by that time provide annual status reports for fiscal year 2015 as requested by regulations.

But of the 26 Drug Safety Communications the agency issued in that fiscal year, none was based on phase 4 clinical trials, while the majority were made from FDA’s Adverse Event Reporting System (FAERS), which records such events reported by healthcare professionals and consumers. The problem with that system is the lack of scientific corroboration that can confirm the adverse events’ link with the products.

There has been wide criticism that biopharma companies only fund phase 4 projects that they already feel confident about returning favorable results. Marcia Angell, former editor-in-chief of the New England Journal of Medicine, has called them “marketing masquerading as research.” Former FDA Commissioner David Kessler wrote in a 1994 article that: “Some company-sponsored trials of approved drugs appear to serve little or no scientific purpose. Because they are, in fact, thinly veiled attempts to entice doctors to prescribe a new drug being marketed by the company.”