The curious case of the dog that never barks
If almost half the data on drugs is hidden from our eyes, as mentioned in my previous post, why is nobody talking about what’s missing? Isn’t it odd that tons of negative data can disappear so flawlessly with hundreds of eyes peeking over them everyday? Not a researcher that calls for past studies, not a journal that protests lack of publication, not a regulator that nabs the offence?
Unfortunately, not everyone is as clever as Sherlock Holmes to solve mysteries by focusing on what’s missing than what is present. In ‘Silver Blaze,’ the story that revolved around the disappearance of a famous racehorse, Holmes had recognized that none of the people he interviewed had mentioned that the watchdog had barked on the night of the incident. Holmes had concluded that if the dog had not barked, then the dog must have known the perpetrator, and this had led him to track down the guilty party.
But Holmes was an exception. Humans have a natural tendency to focus on what is present than what is missing. Disregard of negative information happens on account of several reasons – not all of them malicious by intent. Many times researchers overlook publishing negative findings wrongly assuming that a study that’s not turned out positive is not ‘exciting’ for other researchers.There’s also the issue of incentives: academics are measured by crude metrics like the numbers of citations for their papers. With positive, ‘high-impact’ studies they can get into glamorous, well-read journals, readership is high, mood is upbeat, et al. But negative findings? They simply don’t bother to publish.
Negative data can also go missing without breaking any laws because of ridiculous loopholes that smart companies can cheerfully exploit, such as in the paroxetine case. When GSK found that paroxetine led to suicidal thoughts in children, it had no obligation to tell the regulators about it because the use of paroxetine in children was ‘off-label.’ And drugmakers only have to report side effects for the specific uses for which a drug has marketing authorization.
Moreover, regulation that subjects trials to mandatory reporting is quite weak all over the world.In the US, the fine for non-compliance is $10,000 a day, which sounds spectacular, until you realize that it’s only $3.6 million a year, which is chickenfeed for a drug bringing in $4 billion a year. And guess what – no such fine has ever been levied, throughout the entire history of legislation.
Another problem is what we can call the ‘chinese whisper’ or the ‘lost in transit’ problem.Many times regulators have all the data regarding the safety and effectiveness of a drug, but all that they make available to practitioners or the public is a thin, crude, and uninformative summary: just a ‘yes’ or ‘no’ about side effects. However, at the core of every trial is the raw data: every single record of blood pressure of every patient, the doctors’ notes describing any unusual symptoms, and so on. The devil, as they say, is in the detail.
While research and regulatory problems persist, the single most important reason why negative data goes missing, is the source of funding. Most of the drug research today is conducted by drug makers, than by government or academia. Almost 75% of USA’s clinical trials in medicine are paid for by private companies. Private funding is not necessarily bad. It can fill in the void created by the State. Galileo’s work in the 16thand 17thcenturies, for example, was supported mainly by philanthropists, including the Pope.
However, industry-funded research is more likely to be biased and commercialized. A pharmaceutical company conducting research on a genetic drug stands to benefit if the drug shows potential for treating Alzheimer. When a private company is paying for the study, it is prone to influence the study’s design or interpretation in ways that subtly favour the drug. This is not my opinion or conjecture, but an established fact. Several studies have shown that industry-sponsored trials are almost always positive, and more likely to benefit the sponsor’s drug than studies funded by government, universities, or charitable organizations.
Astudy by Fries and Krishnan presented at the 2001 American College of Rheumatology meetings looked at all kinds of trials that acknowledged industry sponsorship, in order to find out what proportion had results that favoured the sponsor’s drug. The results section had a single, simple, extreme finding: The outcome from every randomized clinical trial (45 out of 45) favoured the drug of the sponsor!This is not peculiar to the pharmaceutical industry. The tobacco industry has muddled research linking smoking to cancer, the sugar industry has underplayed risks of artificial sweeteners, and so on.
Regrettably, industry’s influence on research does not stop here. Investigators employed by drug makers are often not allowed access to raw data for studies they have themselves designed. They may get a printout of the main results, but the actual analysis itself would be done by statisticians within the companies. As mentioned in an earlier post, researchers were denied access to Surgisphere’s data for analyzing impact of hydroxychloroquine on COVID-19. The researchers’ study had to be pulled back later because of inaccurate conclusions. Imperatively, good decisions in science can only be made when researchers, doctors, and patients have access to all pertinent information. But with increased control on funding, drug companies are shrouding unfavourable information.
Going further, researchers and whistleblowers who have attempted to expose drug research have been given a hard time.Sometimes with legal action, and at other times, through character assassination or loss of professional position. When cardiologist Steven Nissen grew suspicious of health risks associated with GSK’s diabetes drug Avandia, he requested access to original patient-level data, but was denied. When he stumbled upon a cache of data on the Internet revealing that GSK had published only 15 out of the 42 clinical trials it had conducted for Avandia, he reported it through The New England Journal of Medicine. The news made frontpage headlines, and a black box warning was imposed on Avandia. However, Nissen himself was under attack through GSK-employed PR firms.
More than half the scientists at the U.S. Fish and Wildlife Service agree that “commercial interests have inappropriately induced the reversal or withdrawal of scientific conclusions or decisions through political intervention.” And again, I’m not cherry-picking a survey to corroborate my assertion. Check out what investigators across the board have to say.
To quote a popular example, Rofecoxib (Vioxx) was introduced by Merck in 1999 as an effective, safer alternative to non-steroidal anti-inflammatory drugs for the treatment of pain associated with osteoarthritis. Since the early development of rofecoxib, some scientists at Merck were concerned that the drug might adversely affect the cardiovascular system. In internal emails made public through litigation, Merck officials sought to soften the academic authors’ interpretation regarding COX-2 interference in the body. The academic authors changed the manuscript at Merck’s request – for example, they changed “systemic biosynthesis of prostacyclin ... was decreased by [rofecoxib]” to “Cox-2 may play a role in the systematic biosynthesis of prostacyclin.” This is same drug that later caused more than 100,000 heart attacks and was withdrawn from the market.
The application of Chanakya’s saam, daam, dand, bhed techniques to coerce researchers into producing desirable results for Big Pharma is not just a plot of ‘The Aquila Trials,’ but a sad reality of industry-funded research.
Yet, the question whether private funding of clinical research is a boon or a bane is not a sacrosanct yes or no. At any given point in time, it can be answered by analyzing how the phenomenon is playing out in the real world. What is the direction of research? Are the drug makers producing a plethora of treatments for erectile dysfunction, but none for Africa’s Ebola virus? On the other hand, are the State’s forces competent enough to battle a worldwide pandemic such as COVID-19 or do we need all the possible investment, including private funding? Is the government prioritizing military over research?Several of USA’s science-driven agencies have been losing funding. For the first time since World War II, the US government’s share of basic research funding has dipped below 50%, Sciencemagazine reported in 2017. These and several other factors need to be considered in evaluating the balance of private-public partnership in scientific research.
While science has many safeguards in place to catch biases, it pays to remember that funding is a significant cause of prejudice in research, and the biggest reason why almost all the negative data on drugs has disappeared. A little scrutiny can go a long way towards identifying biases that lead to the disappearance of negative data. Because, bizarre as it may be, the watchdog ain’t going to bark.
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