01.11.2010 Natural Health

Pocket Book Research

Research into many pharmaceutical drugs is suspect and heavily influenced by money and other incentives, claims health researcher Peter Dingle PhD

An interesting dimension of pharmaceutical companies' practices is that the same drug companies that reap money from drugs conduct the research, pay the researchers and control the research - including what is, and is not, published. Drug companies engage in censorship, bribery, corruption, fraud, suppression of negative studies and all varieties of unscrupulous tactics to sell their products; there are literally hundreds of studies that demonstrate this situation. At the simplest level, most medical research is financed by pharmaceutical companies seeking support for drugs that are either on the market or in development.

Research - seen as the beacon of modern medicine - is far from pure. It is not the black and white we expect it to be. The huge amounts of money involved in pharmaceutical research, along with strong vested interests, make it highly likely that there will be bias. One would have to be naive to believe that the pharmaceutical companies do not influence the outcome of research when billions of dollars are involved. Yes, billions of dollars.

The influences employed include participant bias, ghost writing, pressure on researchers or, even worse, financial incentives for researchers, fake journals and just about any underhanded means by which a pharmaceutical company can achieve the outcomes it desires, including pressure on or removal of dissenting academics. Once the pharmaceutical companies are selling the drugs, they are supposed to conduct follow-up studies to keep track of potential side effects and negative outcomes, but they rarely do. Some of the research required to get a drug approved is conducted for only 10 or 12 weeks on medication people are instructed to take for a lifetime. No studies have been conducted on what happens when an individual takes a combination of these drugs, as many people do. The research - and yes, I am a researcher - has literally become the de facto promotional and public relations program for pharmaceutical companies.

After two decades as an editor of The New England Journal of Medicine, one of the most prestigious medical journals in the world, Marcia Angell wrote, "It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines." In 2008 she wrote, "Over the past two decades, the pharmaceutical industry has gained unprecedented control over the evaluation of its own products. Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer."(1) This is a person on the front line of the best medical research in the world. Little wonder the rest of us don't have confidence in the research.

Researchers are influenced by money

There is strong evidence that researchers' financial ties to pharmaceutical or tobacco manufacturers directly influence their published positions in supporting the benefit, or downplaying the harm, of a manufacturer's product. For years, biased industry sponsored research on environmental toxins, such as lead and tobacco smoke, was used to thwart public health responses to these hazards.(2) We now know that the same thing is happening with pharmaceuticals. It is common to see researchers conclude how effective certain drugs are, even though the benefit of the drugs is known to be one percent or less… absolutely nowhere near being clinically effective. Then one reads the affiliations of the researchers and their associations with drug companies. It is not uncommon to read an abstract that gives a glowing report of a drug, yet actually contradicts the findings presented in the paper. Unfortunately, many busy people, including GPs, read only the abstract.

A serious question of ethics arises as a result of the strong link between the authors of most of the studies, at least the ones showing positive results, and the pharmaceutical companies. The disclosure of the associations reads like a Who's Who of the pharmaceutical industry. The biographical summary of a lead author in a recent British Medical Journal article read "…is a consultant for Genentech, Kowa, Martek, Merck, and Merck/Schering-Plough, and serves on the board of directors for Aegerion and Arisaph. He is a member of DuPont's health advisory board and serves on the data safety monitoring board for Novartis."

The Journal of the American Medical Association researched the connection between the pharmaceutical industry and authors of clinical guidelines. More than half the authors received financial support from the pharmaceutical industry to conduct research. And 38% served as employees or consultants for a pharmaceutical company. Despite the so-called scientific rigor of these studies, the authors' financial and other ties to big drug companies open them to many serious biases.

A recent example of corrupt research is researcher Scott Reuben, who promoted the use of the non-steroidal anti-inflammatory drug celecoxib. Dr Reuben fabricated the reports and laboratory data for 21 of 72 published articles related to celecoxib. The research was funded by Pfizer, which markets celecoxib as Celebrex®.(3)

The companies select who goes into the trials

Many drug studies, even "random" studies, rely on selection of participants for optimal outcomes. Researchers select people who might be the healthiest or more likely to show positive results from a particular drug. This is obvious in selecting participants who are not on any other medication. In a truly "random" study, many people would be on other medications, maybe even four or five different types. Yet, in these trials, medical staff are often paid to engage people who will produce the best results - the better the results, the more money from repeat business for the drug companies.

In these studies, participant selection is critical to the honesty and fairness of study results. One study of participants in clinical trials found that 81.3% of exclusions in trials were based on common medical conditions.(4) So if you had a common medical condition, like most people who take medications, you would be excluded. A healthy person with elevated cholesterol is likely to give the best results and show the least side effects from taking statins. Patients were excluded due to age in 72.1% of all trials (60.1% in pediatric populations and 38.5% in older adults). Though older adults are the main market for these drugs, they tend to be more susceptible to side effects. Individuals receiving commonly prescribed medications were excluded in 54.1% of trials.(5) Based on such selection criteria these drugs should not be used with any other medication, yet they are. Gender was grounds for exclusion in 39.2% of trials. In a study of all exclusion criteria, less than half the criteria was graded as strongly justified in the context of a specific study. Exclusion criteria were not reported in 12% of trials; industry sponsored trials were more likely to exclude individuals due to concomitant medication use, medical comorbidities and age.(6) So much for the reliability of "random" trials. Based on such exclusions, these drugs should be used only on young males who have no health conditions and who are not on any other medications. This becomes a major issue when one considers that these studies are also used to determine the rates of side effects. Excluding older people, women and those not on other medications, cuts out 70% or more of the drug users and severely underestimates potential negative side effects.

Even if the experiments did not have these biases, many drugs are approved for use on the basis of a surrogate outcome.(7) For instance, a drug may be approved for use to fight cardiovascular disease because it lowers cholesterol. While the link between cholesterol and CVD is now unclear, it is also not clear that we understand all the associated issues with reducing cholesterol through pharmaceutical intervention. Consequently, drugs are approved to combat CVD by lowering cholesterol despite the fact that these drugs have never been shown to have even a 1% benefit of reducing the risk of a cardiovascular disease.

The follow-up studies that are never conducted

After the clinical trial process is complete and appropriate approvals have been given, it is often a requirement for drug companies to continue with trials or monitoring, or both, so that more data may be gathered regarding a drug's efficacy and safety. Unfortunately, this does not always happen. The Food and Drug Administration (FDA) in the US reported that in 2007 only 29% of the required post-marketing studies had been commenced. Knowing that occasionally drugs are removed from the market because safety issues become apparent after marketing begins, it is disturbing that more than two thirds of drugs are not being adequately monitored to detect potentially harmful effects at the earliest possible moment. These companies have a responsibility to conduct the tests. They rush the early tests through to get the products onto the market, then delay tests that show whether the drugs really work.

Ghost writers and skeletons in the closet

To keep abreast of safety profiles, physicians rely on medical literature. The integrity of the study authors and the journals is critically important to make sure that doctors have the best and most honest advice. A colleague's name on a peer-reviewed article gives confidence for making prescribing decisions. Authorship in medical publications establishes accountability, responsibility and credit. Misappropriation of authorship undermines the integrity of the authorship system and is blatantly dishonest. At university we call this plagiarism and a student who engages in this - even once - instantly fails. In the medical world, those who plagiarise are rewarded with money and prestige.

In a review of 809 medical articles, 11% had evidence of ghost authorship, although the authors of the review suggest that this is likely a gross underestimation.(8) In a follow-up study in 2008, six of the top medical journals published a significant number of articles that were written by ghostwriters financed by drug companies.(9) Even sources of information such as the prestigious Cochrane reviews, the "gold standard" for unbiased analysis of treatment options, reported a "substantial proportion of reviews had evidence of honorary and ghost authorship."(10) That is, in the best medical journals in the world, the drug companies are often writing or making significant contributions to the papers, without being identified. This practice is corrupt and, unfortunately, increasingly prevalent.

Most disturbing, transcripts of pharmaceutical and medical education sessions or communication company documents made public as the result of recent lawsuits against pharmaceutical companies provide chilling reading for journal editors, clinicians and patients, indicating the myriad ways that pharmaceutical companies may potentially manipulate the biomedical literature. (11) The New York Times reported (12) that the Annals of Internal Medicine paper on a Vioxx® clinical trial failed to include the deaths of several patients.(13) The paper's first author admitted, "Merck designed the trial, paid for the trial, ran the trial." This is not limited to one drug or one company. The clinical trial manuscripts related to rofecoxib (Vioxx®) were often prepared by unacknowledged authors. These manuscripts were subsequently attributed authorship to academically affiliated investigators; the latter did not often disclose industry financial support.(14 ,15)

Another investigation found that, over several years, Wyeth pharmaceuticals hired medical ghostwriters to create favorable articles about hormone replacement therapy. The company would later add the name of a reputable physician, giving the appearance that the physician was the author.(16) The journal Blood has recently begun investigating articles sent to it after concerns were raised over ghostwriting by pharmaceutical companies.(17) The journal found that a pharmaceutical company provided an author with meeting abstracts and copies of relevant articles and compiled tables of results of clinical trials, which the author then used to write the review article. Consequently, the manuscript was rejected. Following up on other papers, within two weeks the journal rejected two additional unsolicited manuscripts.(18)

Selective reporting: what you don't know will hurt you

Then there is the concern of underreporting of negative trials or over-reporting of favorable trials. A 2007 article in the New York Times(19)reported that the drug makers Merck and Schering-Plough had conducted several studies of their popular cholesterol medicine Zetia® which, though they raised questions about the drug's risks to the liver, were never published. The FDA raised questions about whether Zetia® can cause liver damage when used long-term with statins.(20) Zetia® is taken along with statins like Lipitor®, Crestor® or Zocor®. Alternatively, a patient can take a single pill, Vytorin®, which combines Zetia® with Zocor®. Merck and Schering-Plough were already under criticism for not having released data from an important Zetia® study called Enhance.(21) The article reported that the company had not considered the studies scientifically important enough to publish. During the two years that the study results were withheld, consumers purchased $5 billion of Zetia® and Vytorin®. It was only under pressure from Congress and prominent cardiologists that the companies released the full results of the Enhance trial(22). The bottom line of this study is that there is no compelling reason for patients to take either Zetia® or Vytorin®.

Numerous studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favourable results. Many trials were still not published five years after FDA approval. The information in the scientific literature readily available to health care professionals is incomplete and potentially biased.(23)

In a review of 74 registered FDA studies of 12 antidepressant agents involving 12,564 patients,(24) 31% (accounting for 3,449 study participants) were not published. Thirty seven "positive" studies were published and only one study viewed as positive was not published. With only three exceptions, studies viewed by the FDA as having negative or questionable results were either not published (22 studies) or published in a way that conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that only 51% were positive.(25)

There is strong evidence of selective outcome reporting in published reports of randomised trials.(26) Even in randomly controlled trials (RCTs) of comparisons between particular drugs and placebos, the support and financial ties of study authors are associated with favorable findings.(27) Similar findings were reported in a cross-sectional study of 192 published RCTs comparing a statin drug to another statin drug or non-statin drug. RCTs of head-to-head comparisons of statins to other drugs are more likely to report results and conclusions favoring the sponsor's product compared to other drugs.(28)

The scientific literature abounds with information based on biased pharmaceutical studies - enough to fill an encyclopedia. Favourable results are often highlighted, while unfavorable data is suppressed; definitions of primary outcomes are changed; and methods of statistical analysis are modified. The studies overwhelmingly show that the randomised trial literature is skewed toward reporting favorable results.(29) In a major review, a substantial amount of primary outcome data submitted to the FDA was found to be missing from the medical literature. One quarter of trials in a sample was unpublished, predominantly those with unfavorable results. Not only was data suppressed for the unpublished trials, but also an additional quarter of primary outcomes was omitted from journal articles on published trials.

These findings are consistent with two reviews of FDA documents and journal articles.(30, 31) The research shows important discrepancies between the primary outcomes (what researchers are supposed to be looking for), statistical analyses, and conclusions presented in new drug trials versus those reported in the journal articles. The vast majority of discrepancies favoured the sponsor's new drug. This suggests extremely biased reporting.

There is no shortage of research showing various aspects of publication bias as a result of industry sponsorship. This includes data suppression, misrepresentation, manipulation, reporting bias, financial and non-financial competing interests, sponsors' control of study data and publication, and restrictions on access to data and materials.(32, 33, 34, 35)

To overcome some of the biases from the pharmaceutical industry, in 2005 the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrolment as a precondition for publishing the trials' findings in member journals.(36) However, in a recent review of 323 studies, 147 (45.5%) were adequately registered, but registration was lacking for 89 published reports (27.6%); 45 trials (13.9%) were registered after the completion of the study; 39 (12%) were registered with no or an unclear description of the primary outcome; and three (0.9%) were registered after the completion of the study and had an unclear description of the primary outcome. Among articles with trials adequately registered, 31% (46 of 147) showed some evidence of discrepancies between the outcomes registered and the outcomes published. The influence of these discrepancies could be assessed in only half of the studies and, in these, statistically significant results were favored in 82.6% (19 of 23).(37) If the outcomes are not reported, then the research can be manipulated to show positive outcomes - that is, to claim a drug works when it doesn't.

To lower the standard of science even further (if possible), one study found that one company created a fake medical journal called The Australasian Journal of Bone and Joint Medicine in order to promote Vioxx® and Fosamax®. World osteoporosis authorities were named on the editorial board, giving great credibility to what was nothing but a marketing tool. Unsuspecting and busy doctors receiving the literature would be hard pushed to see through the deception. This is exactly what the tobacco industry did 30 years ago.

To sum it up, the studies are rigged from the beginning, and still the doctors trust the research and the drug companies? If it were any other business, these companies would be out of business and no one would believe the information. So why do we do it here?

References:

(1) Angell, M. (2008). "Industry-sponsored clinical research: A broken system." Journal of American Medical Association 300(9): 1069-1071.(2) Sharpe, V.A. (2002). "Science, bioethics, and the public interest." The Hastings Centre Report 32(3): 23-26.(3) Lenzer, J. (2009). "Prominent celecoxib researcher admits fabricating data in 21 articles." British Medical Journal 338: 966.(4) Van Spall, H.G.C., A. Toren, et al. (2007). "Eligibility criteria of randomized controlled trials published in high-impact general medical journals." Journal of American Medical Association 297: 1233-1240.(5) Ibid.(6) Ibid.(7) Ledford, H. (2008). "Drug markers questioned." Nature Review Drug Discovery 452(7187): 510-511.( 8) Flanagin, A., L.A. Carey, et al. (1998). "Prevalence of articles with honorary authors and ghost authors in peer-reviewed medical journals." Journal of American Medical Association 280: 222-224.(9) Wilson, D. and N. Singer (2009). Substitute ghostwriting is called rife in medical journals. New York Times. New York.(10) Mowatt, G., L. Shirran, et al. (2002). "Prevalence of honorary and ghost authorship in Cochrane reviews." Journal of American Medical Association 287: 2769-2771.(11) Berenson, A. (2005). Evidence in Vioxx suits shows intervention by Merck officials. New York Times. New York.(12) Ibid.(13) Lisse, J.R., M. Perlman, et al. (2003). "Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: A randomized, controlled trial." Annals of Internal Medicine 139: 539-546.(14) Hill, K.P., J.S. Ross, et al. (2008). "The ADVANTAGE seeding trial: A review of internal documents." Annals of Internal Medicine 149: 251-258.(15) Ross, J.S., K.P. Hill, et al. (2008). "Guest authorship and ghostwriting in publications related to rofecoxib: A case study of industry documents from rofecoxib litigation." Journal of American Medical Association 299: 1800-1812.(16) Singer, N. (2009). Medical papers by ghostwriters pushed therapy. New York Times. New York.(17) Dunbar, C.E. and M.S. Tallman (2009). "'Ghostbusting' at Blood." Blood 113(3): 502-503.(18) Ibid.(19) Berenson, A. (2007). Cholesterol drug shows no benefit, possible harm. New York Times. New York.(20) Ibid.(21) Ibid.(22) Ibid.(23) Rising, K., P. Bacchetti, et al. (2008) Reporting bias in drug trials submitted to the Food and Drug Administration: A review of publication and presentation. PLoS Medicine 5, e217, doi:10.1371/journal.pmed.0050217.(24) Turner, E.H., A.M. Mathews, et al. (2008). "Selective publication of antidepressant trials and its influence on apparent efficacy." New England Journal of Medicine 358: 252-260.(25) Ibid.(26) Vedula, S.S., L. Bero, et al. (2009). "Outcome reporting in industry-sponsored trials of Gabapentin for off-label use." New England Journal of Medicine 361(20): 1963-1971.(27) Rattinger, G. and L. Bero (2009) Factors associated with results and conclusions of trials of Thiazolidinediones. PLoS Medicine 4, e5826, doi:10.1371/journal.pone.0005826.(28 ) Bero, L.A. and D. Rennie (1996). Influences on the quality of published drug studies. International Journal of Technology Assessment in Health Care 12: 209-237.(29) Rising, K., P. Bacchetti, et al. (2008) Reporting bias in drug trials submitted to the Food and Drug Administration: A review of publication and presentation. PLoS Medicine 5, e217, doi:10.1371/journal.pmed.0050217.(30 ) Turner, E.H., A.M. Mathews, et al. (2008). "Selective publication of antidepressant trials and its influence on apparent efficacy." New England Journal of Medicine 358: 252-260.(31) Lee, K., P. Bacchetti, et al. (2008) Publication of clinical trials supporting successful new drug applications: A literature analysis. PLoS Medicine 3191, doi: 10.1371/journal. pmed.0050191.(32) Al-Marzouki, S., I. Roberts, et al. (2008). "Selective reporting in clinical trials: Analysis of trial protocols accepted by The Lancet." Lancet 372: 201.(33) Angell, M. (2008). "Industry-sponsored clinical research: A broken system." Journal of American Medical Association 300(9): 1069-1071.(34) Bekelman, J.E., Y. Li, et al. (2003). "Scope and impact of financial conflicts of interest in biomedical research." 289(4): 454-465.(35) Bero, L.A., B. Djulbegovic, et al. (2003). "Pharmaceutical industry sponsorship and research outcome and quality: Systematic review." British Medical Journal 326: 1167-1170.(36) Mathieu, S., I. Boutron, et al. (2009). "Comparison of registered and published primary outcomes in randomizd controlled trials." Journal of American Medical Association 302(9): 977-984.(37) Ibid.


Disclaimer
Dr Peter Dingle PhD is an associate professor and researcher who has researched nutritional toxicology for the past 10 or more years. He is not a medical doctor. After completing his honours in environmental toxicology in 1988, he went on to complete his PhD in the same field in 1994. The information he presents is based on the research he and his students carry out at MurdochUniversity where he is Associate Professor in Health and the Environment.

Peter Dingle

Dr Peter Dingle (PhD) has spent the past 30 years as a researcher, educator, author and advocate for a common sense approach to health and wellbeing. He has a PhD in the field of environmental toxicology and is not a medical doctor. He is Australia’s leading motivational health speaker and has 14 books in publication.

http://www.drdingle.com/

https://www.facebook.com/DrPeterDingle/

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