In Bad Medicine PT 3, we looked at the R&D myth that is being used by governments and pharmaceutical companies to ‘justify’ the TPP and other trade deals. Despite the increased patent rights over the past decade we are seeing less R&D, higher drug costs, and increased research into specialty drugs(specialty drugs – that cost up to $500,000 per year – now account for 25% of private drug spending in Canada). Yet, despite this worrying situation the TPP will grant significantly less transparency into R&D practices. The last article left off discussing big pharma’s advertising campaigns which account for more spending than R&D. It also highlighted that advertising a different phenomenon than marketing. To understand why big pharma wants to use TPP to garner less transparency into their R&D, we have to look at the state of clinical trials which have largely become an exercise in marketing. It is not a simple subject, but it is essential to fully understand the current situation which trade deals will further entrench.
*Sample tweet from Big Pharma's Canadian association - In reality IP is crucial for them to make huge profits and price guage, but when it comes to R&D and 'innovation' it is a fable*
In Canada, it has been shown that, “public funding for research has, over several years, been increasingly aligned with industry's goals and practices. A slew of policy initiatives from every level of government emphasize commercializing research. In this environment, the ability of publicly funded science to advance valuable pharmaceutical interventions instead of product line extensions, or independently scrutinize the evidence base behind such interventions, may be compromised.” This comes at a time when, as Professor Gagnon has outlined how, “More than 80% of new drugs do not provide any new benefits over existing products, even though they are sold at higher prices. This is the result when you have a purchasing system that will pay any price for any drug.” A new report by Doctors Without Borders also highlighted, “With current incentive mechanisms, the biomedical innovation system concentrates investment on products that will sell well, and not necessarily on existing public health priorities...The result is a lack of investment in drugs, diagnostics and vaccines to meet the needs of people who can’t afford to pay high prices, or who don’t constitute a sizeable or lucrative market.”
We desperately need more transparency and oversight of R&D practices and the associated clinical trials. While there are researchers and companies doing legitimate and important research, far too often big pharma relies on bad science (as The National showed recently). There is an epidemic of junk science and rented white coats. When it comes to clinical trials it has been documented that industry sponsored trials are more likely to report positive results than independent studies and researchers with financial ties to manufacturers are more likely to express big pharma favorable opinions. A recent journal article showed that, ``Millions of dollars in revenue can be lost if there are delays in getting drugs approved, thus incentivizing sponsors to influence research [design and dissemination] to advance their interests...results favorable to the manufacturer are presented in detail, while unfavorable results are often glossed over or omitted.” It is no surprise than that big pharma wants to keep us in the dark. Recently the industry sought, “to have clinical trial data included in the definition of trade secrets in new EU legislation... The company at the heart of the January 2016 clinical trial scandal in France, which left one person dead and five people hospitalised, also refused to release crucial documents about the trial, claiming that the commercial confidentially of the trade secrets they contained overrode the public interest in knowing the content of the documents.”
We tend to think of doctors, academics and researchers (or science in general) as a neutral and evidence based this is often not the case. While there no doubt are many excellent professionals out there doing quality work, the pharmaceutical industry has completely corrupted the publication and R&D industry. It is easy to generate statistical evidence for most things and get this info published, a fact that a few researchers and journalists have shown. In 2011, a journal article in Phsycological Science claimed listening to The Beatles, ‘When I’m Sixty-Four,’ can make you younger by an effect called “chronological rejuvenation.” The tongue-and-cheek article sought to point out how easy it was to manipulate data to confirm a given hypothesis. In another case with open access journals that didn’t even attempt to skew its flawed research, a Canadian researcher sent out a paper (claiming to be young geologist at the University of Ottawa-Carleton [a university that doesn’t exist] and co-authored by a fiction researcher named Nepean Desert) with glaring scientific errors, ample plagerism and text full of meaningless academic garble (copying and pasting phrases from geology and hematology papers available online). He sent this paper to 18 journals and within 24 hours started receiving acceptances. Some journals claim the article was sent to by an independent expert in the field who gave me a glowing review and would publish his article for a $500 submission fee.
Image Source: http://www.vox.com/2015/3/23/8264355/research-study-hype
But, perhaps the best example comes from a hoax/sting created by science journalist John Bohannon who, “conducted a real — but deeply and deliberately flawed — study on how chocolate affects weight loss. He wrote press releases to alert the media, then sat back and watched who bit. Many news organizations around the world took the bait.” By p-hacking his experiments design he was able to easily attain statistically significant results (P(winning) = 1 - (1 - p)n). Or to put it in a simpler context, Bonannon states, “Here’s a dirty little science secret: If you measure a large number of things about a small number of people, you are almost guaranteed to get a “statistically significant” result. Our study included 18 different measurements—weight, cholesterol, sodium, blood protein levels, sleep quality, well-being, etc.—from 15 people. (One subject was dropped.) That study design is a recipe for false positives. Think of the measurements as lottery tickets. Each one has a small chance of paying off in the form of a “significant” result that we can spin a story around and sell to the media. The more tickets you buy, the more likely you are to win. We didn’t know exactly what would pan out—the headline could have been that chocolate improves sleep or lowers blood pressure—but we knew our chances of getting at least one “statistically significant” result were pretty good.”
While the above examples may seem extreme, they are simply emulating what is a common practice in medical journals and clinical trials by the pharmaceutical companies conducting their R&D (as we’ll see below it is no wonder they want to use the TPP to create less transparency). A new project found that of the 5 most prestigious medical journals, 58 out of 67 articles regarding clinical trials examined had switched outcomes (a great explanation and example of clinical trial `outcome switching` can be found here). At the same time there is now, “growing concern about systematic structural flaws that undermine the integrity of published data: selective publication, inadequate descriptions of study methods that block efforts at replication, and data dredging through undisclosed use of multiple analytical strategies. Problems such as these undermine the integrity of published data and increase the risk of exaggerated or even false-positive findings, leading collectively to the ‘replication crisis.’” And all of this says nothing of the selection of trial subjects being those least likely to have complications (which would limit the approval of a drug). For example seniors are not selected in many cases as they metablize medication differently than adults and may have compounding health issues, even if the drug is destined for use largely by seniors. This is the R&D industry the TPP wants to entrench.
If you still think having less transparency in R&D because of the TPP is not a big deal, the issue of ghost authorship and ghost management should raise the alarm. The next stage of R & D often involves corporate ghost authorship in industry-initiated randomised trials and the subsequent pandemic of gift authorship which entrenched in medical journals. Under the current system there is massive financial incentive for the pharmaceutical industrial complex to produce biased science and massive PR campaigns to influence physician prescribing habits (a topic for a future blog). After clinical trials the next stage of R & D often involves corporate ghost authorship in industry initiated trials and the subsequent pandemic of gift authorship entrenched in medical journals. In his must read article on how evidence-based medicine (one of our health ministers favourite terms) has been hijacked, Dr. John Ioannidis discusses how, “It is sometimes difficult to tell whether a superb CV with a lengthy publication list reflects hard work and brilliant leadership or the composite product of dexterous power game networking, gift authorship.” In this game to get a better authorship positions (many articles will have over 100 so called authors) and prestige, Ioannidis shares an anecdote about the practice with clinical trial authorship stating, “I asked to see the protocol and comment on it. The answer was clear and immediate `Oh, the protocol, why should you worry about the protocol? The sponsoring company has taken care of the protocol already and will also take care of writing the paper. You don’t need to worry about that minor stuff. You shouldn’t waste time with the protocol or editing drafts. We will put your name as an author on the papers, no worries. This is what all prestigious clinical researchers do.’”
It doesn’t stop with medical and scientific articles being ghost authored, pharmaceutical companies also engage in the `ghost management` of medical literature. It has become, ``standard practice for pharmaceutical companies to pay medical communication companies to write articles (based on industry-designed studies), for academic physicians to be paid to essentially sign off on the articles, and then for communication companies to place the articles in prestigious medical journals.`` By controlling the process of research, writing, and publication of these articles through ‘ghost management’, it allows the industry to manage the literature in ways that best serve its interests (profits). Behind the scenes it has been revealed that, “in the past two decades, these companies have developed systems that treat knowledge as a resource to be carefully developed and used to affect the opinions of researchers and practitioners. Publication of pharmaceutical company-sponsored research in medical journals, and its presentation at conferences and meetings, is now governed by ‘publication plans’ that extract more scientific and commercial value out of data and analyses through carefully constructed articles.” The goal is to us company shaped research as a marketing tool to convey the companies message regarding a drug through a host of articles and maximize the publications with positive trial results in prominent journals. Subsequently, any publications have financial ties to drug manufacturers creating a, ``commercial bias resulting from editors’ financial conflicts of interest can affect the content of medical journals and the integrity of the scientific record.`` There are also limited regulatory policies in these publications to require the drug companies to show evidence of clinical relevance of their work or use patient-oriented outcome measures.
It is estimated that, “approximately 40% of journal reports of clinical trials of new drugs (and, more anecdotally, perhaps a higher percentage of meeting presentations on clinical trials) are ghost managed through to publication.” At the same time journals rarely acknowledge or openly show this fact (there has recently been a call by 62 scientists and six organizations to unearth these potential biases and present them in the abstracts). In best case scenarios you will find at the bottom of the research paper (likely beneath the references) information about who funded the study and the researchers’ conflicts of interest if they are disclosed. Overall, what we have is creates a dangerous situation where, “commercial bias in how drug efficacy and safety data are obtained, interpreted, and presented to regulatory bodies and prescribers... currently accepted practices undermine regulatory safeguards aimed at protecting the public from unsafe or ineffective medicines...weak regulatory policies allow for design choices and reporting strategies that can make marginal products look novel, more effective, and safer than they are, and how the selective and imbalanced reporting of clinical trial data in medical journals results in the marketing of expensive ‘me-too’ drugs with questionable risk/benefit profiles.”
An example of this ghost management in a recent case study showed that for the anti-depressant vortioxetine, “the design choices, interpretive strategies, and rhetorical devices employed by researchers with industry ties and published in journals with commercial ties give the reader the impression that a “new” antidepressant is safe and well tolerated, when in fact the data were not collected or analyzed in a way that provides sound empirical support for this conclusion. Additionally, the data on efficacy are not reported in the published trials with the caution that is warranted and that is reflected in the independent meta-analyses. The lowest price for a month’s supply of vortioxetine is USD 253.55; the antidepressants used as active comparators in the RCTs—duloxetine and venlafaxine—are available as generics and cost from USD 14.40 to USD 52.25 per month. Thus, the public will be paying up to 17 times more for a drug that appears to be less efficacious, and is unlikely to be safer or better tolerated than existing alternatives.”
Image Source: http://www.vox.com/2015/3/23/8264355/research-study-hype
Research shows that roughly 30–50% of clinical trials remain unpublished, often years after their completion, and most fail to meet baseline legal disclosure requirements for the FDA. Marcia Angell, the former editor in chief of The New England Journal of Medicine, has described how, ``industry-sponsored research that does not show benefit is very often not published at all. For example, a review (published in NEJM, Jan. 17, 2008) of 74 company-sponsored clinical trials of antidepressants found that 37 of 38 positive studies — that is, studies that showed effectiveness — were published. But of the 36 negative studies — those that failed to show effectiveness — 33 were either not published, or published in a form that wrongly conveyed a positive outcome. The cumulative result of this sort of thing is that both the public and physicians come to believe that drugs are better and safer than they are.``
Sadly, these systematic practices which form the backbone of big pharma’s R&D are largely accepted as normal despite undermining public health. It has been stated that, “as long as the pharmaceutical industry controls the production of knowledge, the interest of the industry will influence the knowledge that is produced . . . . [a]nd nothing short of the radical reimagining of the relationship between research and industry can succeed in eliminating the distortions of the pharmaceutical industry on the scientific literature.”
The results of this system are not pretty. It is no surprise then that of the 434 new drugs approved between 1995-2010 in Canada, 19.4% (84) were subject to serious safety warnings and/or were withdrawn for safety reasons. Dr. Joel Lexchin has written extensively about pre and post market surveillance, or the lack thereof a quality system in Canada, which the TPP would make much more difficult to implement. In regards to post-market surveillance and regulation Canada does have a recent bill entitled “Protecting Canadians from Unsafe Drugs Act” but better known as Vanessa’s Law (complete text here; Q&A summary here). Yet, researchers have noted, “Health Canada seems to want to have it both ways: be seen as a regulator that serves the public interest through a progressive commitment to transparency, yet be trusted by industry to not publicly disclose any clinical trial data which it calls ‘confidential business information.’ Given our experience over the past few months, we think Health Canada may be prioritising the latter at the expense of transparency.” Further, scholars have outlined that, ``Although Vanessa’s Law created new transparency powers, it also legitimated Health Canada’s long-standing practice of treating drug safety and effectiveness information as proprietary. The definition of `confidential business information` in the legislation can accommodate drug safety and effectiveness data provided that the data are not publicly available.``It seems that Health Canada is continuing ,for all intent and purposes, its long held policy of keeping important safety and effectiveness information confidential at the request of the pharmaceutical industry (it should be noted the law also gives the minister of health the discretion to disclose this information to prevent drug related injuries or for the purposes of protecting or promoting human health or public safety).
People have died from this lack of disclosure and the industry corruption of clinical trials when physicians are misinformed. The case of Vioxx being approved is one such case where, “patients are not merely put at risk by the way ghost management uses medical research for marketing purposes: they are actually harmed. Not only does ghost-managed research put trial participants at risk, it threatens the health of millions of patients who take drugs that might otherwise not be prescribed. “ Health lawyer Matthew Herder has explained that, “In some cases, disclosing this evidence might prevent serious harm. Consider Vioxx. Approved in 1999 for treating arthritis, it was withdrawn from markets in 2004 after thousands are estimated to have suffered cardiac arrest and death. Regulatory officials knew of this risk but kept it secret on the grounds it was company property. This practice has to stop.”
It is long past the time when Health Canada and the health minister can turn a blind eye to the predatory and dangerous practices Big Pharma creates through manipulating science for increased profits. The TPP stands to make the R&D process more opaque at the request of drug companies, this is fundamentally unethical and anti-democratic. We need to lift the veil on the real R&D costs and strengthen our governments’ ability to hold the big pharma to account to protect our public health. At the same time it is essential to look sensibly at our medication use. It is important to note that this doesn`t mean going to the other end of the spectrum and relying on dangerous pseudo-science for miracle cures. No one wants to go back to the days before anti-biotics where a small infected cut could lead to death, but this also doesn`t mean we have to blindly swallow bad medicine. We need to have better pharmaceutical knowledge produces and improved prescribing practices from physicians. So how do we get there?
Accepting the failures of our current pharmaceutical policy and signing trade deals that increase patent monopolies and increase drug prices is a political choice. While universal pharmacare cannot fix all the problems, it might be a tool to help get things on the right track. But, this means not simply looking at pharmacare through a cost-savings lens which, while important, should not be driving this major policy reform. We have the power to create real change and robust institutions that force big pharma to provide quality clinical trial data, proven therapeutic benefits, and ensure the safety of public health. Without a wholesale change in how we govern this industry, half measures like a new formulary, catastrophic coverage or bulk buying will simply be more of the old.