RokStories Industry-Funded Research For Antibacterial Products: Boon Or Bane?
By P.J. Heller

As hospitals struggle to reduce drug-resistant bacterial infections among patients, one of the tools they have turned to is germ-killing chemical chlorhexidine.

But a recent Reuters news report raises serious questions about studies conducted by medical researchers promoting the use of the powerful antiseptic – studies paid for by companies that manufacture and market the antibacterial products.

“Makers of products using chlorhexidine to fight bacteria in hospitals provide support for scientists who repeatedly find those products to be very effective – even as concerns about safety have mounted,” the special report by Reuters said.

“. . . as use of chlorhexidine products has grown, so have concerns about their effectiveness and safety ¬– and about the role of industry-backed research in promoting them. The industry money funding chlorhexidine research muddies the message of the results, in the view of many health experts,” the report said.

The news agency cited funding for a patient study on chlorhexidine wipes provided by manufacturer Sage Products, at Rush University Medical Center in Chicago. The findings, published in 2006, reported that the wipes were highly effective at preventing vancomycin-resistant enterococci (VRE), an antimicrobial-resistant bacteria which most often occurs in hospitals. VRE outbreaks, which have occurred worldwide, can be fatal.

Following publication of its study, Rush University Medical Center received a $1 million donation from a family foundation of Sage’s founder. According to Reuters, the money was to go to Dr. Robert A. Weinstein, the senior scientist who conducted the chlorhexidine study. The foundation said the money was to be used for research and that there were no strings attached to the funds.

“Since then, Sage has provided funding and millions of dollars in wipes for studies by Weinstein and his colleagues,” Reuters reported, noting that during that time “ . . . Weinstein and his colleagues have published 11 articles on six trials that endorse daily washing of patients with Sage’s patented wipes – an ‘off-label’ use, as the U.S. Food and Drug Administration (FDA) has approved the wipes only for cleaning patients before surgery.”

Those findings, as well as others that were published following industry-backed funding and support, raise questions about their validity and about whether results may have been skewed, according to health experts.

Such concern is nothing new, having been raised in other industry-backed research projects, such as for infant formula, tobacco and alcohol.

“Opinions are divided on whether research and educational material funded by the tobacco, alcohol, or infant formula industries can be scientifically sound or whether it is inevitably tainted,” the National Institutes of Health Opinions noted nearly a decade ago.

For his part, Weinstein, an infectious-disease specialist at Rush, told Reuters that Sage did not meddle in his research or have any input into his findings. He also said he published a brief negative reviews of Sage’s products in a European journal in 2010, according to Reuters. Many of his studies were co-sponsored by the Centers for Disease Control, which was “looking over my shoulder.” he told the news agency.

Nevertheless, the World Health Organization suggests that “pharmaceutical company funded research is more likely to show results favorable to the product being studied than research funded from other sources.

“There is an association between the opinions of investigators about products and their source of funding but causality has not been established,” WHO said.

Questions about industry-funded medical research were also raised in a 2012 article in Scientific American.

“Many clinical research studies are funded by pharmaceutical companies and there is a general perception that such industry-based funding could potentially skew the results in favor of a new medication or device,” it said. “Pharmaceutical companies or device manufacturers need to increase the sales of newly developed drugs or devices in order to generate adequate profits. It would be in their best interest to support research that favors their corporate goals. Even though this rationale makes intuitive sense, it does not necessarily prove that industry-funding does influence the results of trials. However, there is also data to support the fact that the funding source does seem to correlate with the outcomes of clinical trials.”

The Reuters article pointed out that declining government funding for medical research made industry support even more necessary. Nearly 75 percent of all funding for clinical trials in the United States currently comes from corporate sponsors, according to health experts.

There is also a lot of money is at stake for companies that market antiseptics and disinfectants such as chlorhexidine wipes. BCC Research estimates that the global market for those products will increase to $7.9 billion in 2020, up from $5.6 billion in 2015, a compound annual growth rate of 7 percent during those five years.

Of particular concern with the studies, according to Reuters, was that while industry-funded research has found chlorhexidine products to be extremely effective, questions have been raised about effectiveness and safety.

“Despite all the promising study results, the number of hospital-acquired drug-resistant infections has remained stubbornly high,” Reuters noted.

In February, the FDA issued a warning about possible allergic reactions to products containing chlorhexidine. Some deaths were reported, according to Reuters.

The FDA had issued a warning in 1998 to healthcare professionals about the risk of serious allergic reactions with products, such as dressings and intravenous lines, that contain chlorhexidine gluconate.

In its most recent warning, the FDA said that "rare but serious allergic reactions have been reported with the widely used skin antiseptic products containing chlorhexidine gluconate. Although rare, the number of reports of serious allergic reactions to these products has increased over the last several years.”

The FDA asked manufacturers of over-the-counter antiseptic products containing chlorhexidine to add a warning label to their products about the risk.

Reuters reported that the number of adverse events reported to the FDA with possible links to chlorhexidine nearly tripled between 2007 and 2016 from an average of 85 per year to 226; the number stayed fairly even for the first seven years but then jumped in both 2015 and 2016. It noted, however, that a “reported event” may not be caused by the product and that not every adverse event is reported.

Among adverse events cited included anaphylaxis shock (120 reports), skin irritation, rashes and burns (325 mentions) and life-threatening events (48 reports). Seven deaths were reported.

The chlorhexidine product ChloraPrep was cited for about one-third of the allergic reactions, Reuters said. The product was originally sold by CareFusion; the California company was acquired in 2015 by Becton, Dickinson for $12.2 billion.

CareFusion in 2014 agreed to pay the U.S. government $40.1 million to settle allegations in a whistleblower suit that it paid kickbacks and promoted its products for uses that were not approved by the FDA.

The allegations centered on CareFusion’s payment of $11.6 million in kickbacks to Dr. Charles Denham to get him to “recommend, promote and arrange for the purchase of ChloraPrep by healthcare providers,” according to the Justice Department. At the time, Denham was the co-chair of the safe practices committee at the National Quality Forum, a non-profit organization that reviews, endorses and recommends standardized healthcare performance measures and practices.

In 2015, the Justice Department announced that Denham had agreed to pay $1 million “to settle allegations that he violated the False Claims Acts by soliciting and accepting kickbacks.”

“Kickback schemes undermine the integrity of medical decisions, subvert the health marketplace and waste taxpayer dollars,” said then-Acting Assistant Attorney General Benjamin C. Mizer. “Doctors and other healthcare professionals who accept illegal inducements undermine the public’s trust in federal healthcare programs . . .”

There was no determination of liability in either settlement, Justice Department officials said.

In 2008 – and again last year – Sage issued a recall of its chlorhexidine wipes because the chemical could be contaminated, Reuters reported. The recall was sparked after the wipes were linked to infections by Burkholderia cepacia, a known cause of infections in hospitalized patients and which are often resistant to common antibiotics. Six patients involved in a study funded by Sage were among those infected due to the contamination.

That 2008 recall prompted a temporary halt in the Sage study, according to Reuters. Weinstein described the recall as a “treatment interruption” in a 2013 article in the New England Journal of Medicine and said the wipes “were safe and effective.” He made no reference to the six B. cepacia infections, Reuters said.

Dr Michael W. Climo, lead author of the study and a professor at Virginia Commonwealth University, told Reuters the infection references were deleted from the manuscript “for brevity” and “because they didn’t directly relate to the wipes’ effectiveness in reducing drug-resistant infections.”

Sage, founded in 1971, was acquired for $1 billion in 2012 by Madison Dearborn Partners, a private equity investment firm. Four years later, in 2016, Sage was acquired by the Stryker Corp., a medical technology company based in Kalamazoo, Mich., for $2.7 billion. Sage is a business within the Stryker Medical Division.

That same year, Sage expanded its voluntary worldwide recall of its chlorhexidine wipes due to potential product contamination with the bacteria B. cepacia.

“Topical administration of a product with B. cepacia may cause serious infections in patients whose bodies cannot fight disease or in hospitalized patients, as well as certain other patient groups,” the company said. “These infections could be life-threatening.”

The U.S. is not alone in having concerns about chlorhexidine. In 2012, the British government warned of the risk of anaphylactic reaction due to chlorhexidine allergy. According to Reuters, the number of adverse events jumped from 14 in 2007 to 117 in 2016.

“The MHRA (Medicines and Healthcare products Regulatory Agency) has received a number of reports of anaphylactic reactions following the use of products containing chlorhexidine,” it reported.

In March, a month after the latest FDA warning, Ireland’s Health Products Regulatory Authority (HPRA) also issued a warning about the risks associated with medical devices containing chlorhexidine. The HPRA said the antiseptic agent had recently been associated with “serious but rare anaphylactic reactions due to chlorhexidine allergy” as well as "severe chemical injury and burns in premature infants.”

Meantime, Reuters reports that debate continues over the benefits of bathing patients with chlorhexidine wipes. Studies co-written by Weinstein of Rush University Medical Center endorsed that practice, saying that adult patients bathed with Sage’s wipes showed a decrease in drug-resistant cultures and that the wipes reduced MRSA (Methicillin-resistant Staphylococcus aureus) cultures in intensive-care units. MRSA infection is caused by a type of staph bacteria that's become resistant to many of the antibiotics used to treat ordinary staph infections.

According to the study, “Daily bathing with chlorhexidine-impregnated washcloths significantly reduced the risks of acquisition of MDROs (multidrug-resistant organisms) and development of hospital-acquired bloodstream infections.”

Others have questioned the way the study was conducted and the possible risks of using chlorhexidine every day. Among concerns was whether antibiotic-resistant bacteria could also develop a resistance to chlorhexidine.

Reuters said the Sage wipes are approved by the FDA for cleaning skin before surgery but not for universal daily bathing. However, it said the company can advise medical practitioners about such an off-label use, leaving it up to them to decide whether to use the wipes for off-label purposes.

A federal lawsuit in 2014 against Sage, by a fired employee, alleged the company was involved in off-label marketing by attempting to get researchers and others to promote daily bathing of patients. The suit was settled last year but terms weren’t disclosed, Reuters said. It said Stryker issued a written statement saying “Sage denied and continues to deny the allegations brought forth in the suit.”

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