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Side Effects, Effectiveness, Corporate Medicine

Cymbalta, white bar is the journal reported side
effects, dark raw bar is the data collected

This graph is the tip of the iceberg.  First pharma does not actively solicit in a phase iii clinical trail all the side effects, or encourage reporting of them via a patient questionnaire.  Often serious side effects and minor ones are grouped together given a less serious heading.  Finally the trials are too short to get figures on deaths, cancer, heart attacks, and which such categories are missing in longer trials.  Another bias is that those who drop out (cease taking Cymbalta) are not sought after to find out why they dropped out of the study.  Trials are ran for marketing objectives.  The results of the trial for the blockbuster Cymbalta is owned by Eli Lily who resists all attempts to make the raw data public.

Side Effects, Effectiveness, Corporate Medicine          http://healthfully.org/rc/id9.html (7/13/13-jk)

1)   A fair assessment of side effects and benefits of a drug treatment requires accurate, balanced, essential, and easily accessible information.  On the one side we have many conscientious doctors; on the other side those who are PhARMA1 “friendly”.  PhARMA has gained nearly total control of the production of information about their products:  the research, the journals, the textbooks the media, the FDA, administrators, treatment protocols, and the doctors’ continuing-education classes.   Their control of the production of information functions to maximize profits.  For general, concise summation issue-by-issue account of what is wrong with corporate dominated drug industry read Marketing Science—with links to journal articles.  That article confirms Harvard Prof. Dr. Marcia Angell's assessment:  We certainly are in a health care crisis; ... If we had set out to design the worst system that we could imagine, we couldn't have imagined one as bad as we have.”   What follows supports Dr. Angell’s assessment:  an account of the labyrinth of deceit concerning side effects and effectiveness of drugs woven by Big PhARMA[1].  Her book, The Truth About Drug Companies, confirms the same.  For people to make prudent drug choices they need to know the state of health care; an informed skepticism is essential.   Several documentaries confirm this assessment; two excellent ones are Money Matters and Big Bucks, Big Pharma.  A healthful skepticism along with healthful advice is a starting point for informed medical choices.  


 2)  In the study of 22 elite athletes with familial hypercholesterolemia (over twice the normal LDL level), 73% did not tolerate the treatment; viz. they wouldn’t continue to take a statin, though there condition is life-shortening. They had a mutation in FH, LDLR or the ApoB which regulates the production of cholesterol. The article describing their treatment  found that:  “Regardless of the biochemical background statin therapy and top athletics seem to be almost incompatible.”  Two studies of insured elder found long-term compliance of 25 & 20%. Yet medical textbooks write of statins “Safe, effective, and well-tolerated … that treat disorders of lipid metabolism” (Braunwald, Heart Diseases, 8th Ed, p 2286).  This is the message taught in textbooks, at the continuing education classes for physicians, and it is supported by “marketing science” in the journal articles.  Unfortunately, the safe, effective, once-leading treatment, a mega dose of Niacin (vitamin B3) is not recommended, and when requested, the doctor’s advice is fundamentally wrong in ways discourages its usage.  Thus niacin has only 3% of the market for treatment of hypercholesterolemia.  Statins were original approved by the FDA for ONLY familial hypercholesterolemia (for good reasons).  Once approved, the door was opened wide.[2]   Marketing works, thus the deceptions of well-tolerated has become accepted as the truth.

 3)  Not Tolerated is a very low standard for side effects:  it counts only those who stopped taking the drug because of side-effects—often without listing the causes of dropping out.  An even lower standard is hospitalization for side effects.   Even lower is a study of Warfarin  that counted as a stomach bleed only those who required a transfusion of 2 or more pints of blood—the same standard was used for Plavix (the second most profitable drug).  The Plavix & Warfarin sales reps will use this result, without mentioning the transfusions, to inform the physician that their drug is safer than aspirin.     

4)  Going up the ladder from not tolerated, the next higher standard is self-reporting, either when asked or volunteered.  Even higher would be self reporting based on having the subject periodically fill-out questionnaire that lists all likely side-effects.  The highest standard--in an ideal world--would be an active study of the general population of patients likely to use the drug in a clinical setting, with special subset of the elderly & frail.  This study would include physical and mental tests (such as treadmill and memory) and analysis for of our body’s biochemistry pathways or metabolism would likely be affected by the medication, e.g. statins block the mevalonate pathway thus affect CoQ10.[3]  FDA approval ought to be contingent  upon a thorough, independent evaluation.  People ought to come first.  But given that the market 

place is against side effects and we have a corporatist state, the standards of scrutiny are a façade, and deception is the norm.  What follow in this expose are four illustrative examples of PhARMA’s marketing ploys.

5)  When the 800 pound gorilla[4] wants to hide the extent of side effects, they do.  Roche in 2011 failed to assess 80,000 reports from physicians on side effects including 15,161, deaths and to forward them to the European Medical Agency EMA), as required by law.  In June of 2012 the EMA began an investigation.  A fine of 5% of sales is legislated in Europe.  The FDA has a similar law requiring the reporting of adverse events, but fines are not legislated.  (Have you heard of this scandal in our corporate media?).  This is the first case in over 5 years investigated by the EMA.  Given the PhARMA friendly nature of the FDA and EMA, undoubtedly most doctors don’t go through the trouble of voluntarily filing reports.  Physicians in Europe and the US are not required to report side effects to the regulatory agency or Drug Company.  Nevertheless given the voluntary system, “more than 525,000 unique patient reports were submitted to AERS [FDA’s report monitoring system] in 2010, with 9.6% of those adverse events resulting in patient deaths and nearly 21% resulting in patient hospitalization….  Drug safety professionals estimate that only 10% of adverse events are reported to the FDA every year, thus grossly underestimating the number of actual adverse events associated with a medication (Heinrich, 2000).”  Many side effects are not listed, others considered rare (though they aren’t), and with multiple drugs being taken, even a conscientious physician will grossly under-report side effects.  Other side effects are considered part of the condition, as the example of statins increasing the risk of death from a heart attack, especially among the elder—a fact denied by a company sponsored studies and their thought leaders[5].  Quite a tip of the iceberg!       

6)  The problem goes further than PhARMA sitting on side-effect information sent to them from doctors.   Everything is measured by its effects upon marketing.  For example, Phase III studies (funded by PhARMA who writes up the results) generates raw data[6] that will be submitted to the FDA--and like foreign regulatory agency—to demonstrate that their drug is better than a placebo (nothing at all).  There is no requirement that they submit all of the early research including those for phase I & II[7].  Phase III studies are done for the sake of gaining patented exclusivity from the FDA.  The FDA receives the raw data and decides if the drug as tested is slightly better than nothing at all, a placebo.  Side effects at this stage of review are rarely factored into the evaluation.  Once the drug is approved for a particular use, the study usually is published for the sake of marketing the new drug (phase IV studies are done after approval).  Unfortunately the FDA does not review the journal articles that are based upon the raw data submitted to the FDA in the phase III studies.  Moreover, the journals never receive the raw data (unlike submission in the other sciences), thus the journal’s review of the article cannot effectively uncover bias.  Knowing that there is no effective review, the marketing departments of drug manufacturers freely manipulate the results to promote the just approved drug.  An independent review of 37 phase III studies based upon the raw data (which was obtained from the FDA under the freedom of information act) compared the raw data to the journal articles.  The five scientists who did this investigation of raw data found for phase III Studies there was an average bias of 32%--range 11% to 69% (in NEJM Jan 2008).  There are many ways to get the paid for results.  For example, in selection 9) Merck eliminated 1/3rd of those given Lipitor, because of reaction which revealed through testing would have produced a negative outcome.  Remember, bias and the façade of review when reading medical journals, and when hearing claims from the media and physicians that a drug is safe and effective.  Consider the limitations placed by the withholding of the raw data, when making a treatment decision. 

7)  The further we look into research and publication of medical science, the corporate difference is observed.   The vast majority of clinical studies published in journal are phase IV studies, which are designed by marketing departments solely for the promotion of sales. Nearly all of these studies are well below the standards in phase III studies.   Some phase IV studies are submitted to the FDA for extending patent life (see Harvard Prof. Marcia Angell’s book The Truth about Drug Companies and How they Deceive Us for development of this complex topic).  Some are done to show that their drug is safer than an alternative, often patent—another area of great abuse.[8]  Most are done to support new, off-label uses (not approved by FDA), which the sales reps and thought leaders7 of the pharmaceutical companies have a their drug is safer than an alternative, often patent—another area of great abuse.[9]  Most are done to support new, off-label uses (not approved by FDA), which the sales reps and thought leaders7 of the pharmaceutical companies have a right to use to promote their drug, a thing that their employer can’t actively do (another regulation with a gaping hole).   In most cases off-label uses of a drug exceed the sales for the FDA approved uses.  Many of the phase-IV studies are not studies at all, but merely a way to reward loyal doctors by paying him for partaking in the study.  He then fills out a questionnaire about the drug’s effectiveness.  It is also a way to get a doctor to prescribe their drug.  Often the study is published in an obscure journal with low standards.  These pseudo-science findings are then used to promote the drug.       

8)  There are many, many ways of down-playing side effects.  The most effective way is to sell the drug’s perceived benefits.  The perceived benefit of lowering coronary events has made statins the most used family of drugs.  By 2007 the world-wide sales of Lipitor was $131 billion.  Fully 50% of men and 17% of women in the age group 65-74 have taken a statin drug in the prior 30 day during the period 2005-2008, and 43% of men and 36% of women 75 and above.  A small chorus warns that Statins are not worth taking.  They are ignored by the press, and buried under a mountain of PhARMA financed studies. The large, seemingly-scientific TNT (Treating to New Target) Study (2007), in 2007, in 2006, in 2006, also earlier in 2005, and other articles, it produced ammo for thought leaders and sales reps pushing Lipitor, who educate doctors on newly discovered benefits of taking higher doses of Lipitor and treating lower levels of cholesterol (expanding the category) and the American Heart Association obliged PhARMA.      

9)  Pfizer didn’t bury all the details of the TNT Study.  The British Medical Journal (BMJ) article questioned the conclusion of the TNT study that “nearly everyone ought to be on a statins”.  The 4 authors explained Selection bias for inclusion in the study (2006):  The low frequency of side effects in the TNT trial compared with the IDEAL trial may be explained by the way patients were selected for treatment. In the TNT trial more than 3000 people were excluded because they did not fulfill the criteria, already had raised aminotransferase concentrations, cancer, or another disease associated with a limited lifespan, or for "other reasons. After one-to-eight weeks' treatment with low dose atorvastatin [Lipitor], an additional 5429 patients were rejected, including 197 with non-fatal clinical endpoints, 193 with adverse events, 69 who did not comply with the treatment, 195 who had ischaemic events, 15 with fatal clinical endpoints, and 373 for other reasons. No information was provided on the nature of the reason for excluding 3,000 for “other reasons”. Similarly, it is not clear which side effects later caused 7.2% to stop the treatment.3  Finally, of the 18,468 patients originally screened for the TNT trial, only 10 003 (54%) were selected, whereas for the IDEAL trial the number was 91.7%, meaning that the patients studied in the TNT trial were much healthier than those included in the IDEAL trial and also than those seen in the doctor's office.”    Medical Journals cannot challenge/offend their advertisers who are also the source of articles, and their editors know this.  Excluding people from a study for to obtain results is well below the standards of science, but not medicine. The prestigious Lancet published[10] (among others) wrote a favorable review of the TNT study.  Given this violation of ethics, what confidence can be placed in Merck’s Zocor 1994, very profitable Scandinavian Survival Study? Medical journal articles must be viewed as marketing tools, with no way of confidently discerning what is accurate.   Corporations rarely in the 60’s controlled clinical trials, they funded medical schools to do them. 

10)  Metastudies put together the “best” published articles and arrive at the averages.  But most are of these done by PhARMA friendly doctors.  Protocol issues in these metastudies are buried because they group different doses, different members in a family of drugs (such as progesterone and MPA for HRT), and the universal bias of the journal articles results remains—average positive bias of 32% (see #6 above).  When the critical, prestigious, non-profit, organization, the Cochrane Collaboration, which specializes in metastudies, though not PhARMA friendly, unfortunately fails to adequately address these issues.  Cochrane and Worst Pill, though failing to challenge the web of corruption, provide valuable guidance with a critical slant to physicians and the public.  They will often when the evidence is clear challenge treatment protocols when supported by convincing evidence. 

11)  Cochrane, for example, found gross inconsistencies and the very suspect fact that 80% of studies by Roche’s Tamiflu were unpublished.  But these missing studies can not fix the inadequacies since PhARMA owns the raw data and does not share it.[11]  Cochrane requested missing studies in 2009 from Roche on Tamiflu, a treatment of influenza A and B viruses.  They were told it would be supplied.  In 2012 they reversed their position on Tamiflu after not receiving the data from Roche.  This is understandable given that the evidence is thin for Tamiflu’s effectiveness.  Hardly enough to justify the billions of dollars that have been spent taking that drug, and billions more by governments stockpiling the drug following the avian-flu scare.  Wikipedia:  The efficacy of Oseltamivir [Tamiflu] is disputed, as a significant amount of its clinical trial data remains unpublished by the drug's manufacturers. A meta-analysis done by Kaiser et al. and supported by manufacturer Hoffmann-La Roche, was published in 2003.[13] It concluded that oseltamivir can prevent complications of influenza such as pneumonia if it is taken within 48 hours of the first appearance of influenza symptoms. Kaiser's study was based on a summary of ten randomized controlled trials, of which only two had been published.  The unpublished nature of most of the included trials would later cast doubts on Kaiser's conclusions.”  In addition, “As of December 15, 2010, the World Health Organization (WHO) reported all 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir.[5]…. In the 2008-2009 flu season, the proportion of resistant H1N1 increased to 99.4%.... The Cochrane review reported a meta-analysis of 20 studies which showed oseltamivir offered mild benefits in terms of duration of symptoms for healthy adults if taken within 24 hours of onset of symptoms [few see a doctor that quickly], but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza.[14] These findings relate only to its use in healthy adults with influenza, not in patients judged to be at high risk of complications…. A subsequent Cochrane review, in 2012, maintains that significant parts of the clinical trials still remains unavailable for public scrutiny, and that the available evidence is not sufficient to conclude that oseltamivir decreases hospitalizations from influenza-like illnesses.[4]  They reversed their finding of an early meta-analysis which found Tamiflu effective.  The later review found not only evidence lacking but also serious discrepancies.[12]  To resolve this Cochrane asked Roche to supply the raw data in 2009, and Roche agreed.  Then after 2 years, the request was made again.  Roche now in their response attached the condition that Cochrane must agree not to make public the information.  Cochrane declined.  “As of October 2012, 60% of Roche's clinical data concerning oseltamivir remains unpublished.[17]”, Cochrane’s position:  “We believe that until more is known about the mode of action of neuraminidase inhibitors, health professionals, patients and other decision makers need to reflect on the findings of this review before making any decision about the use of the drug.”  Cochrane certainly is not the last word in critical analysis.  They missed the WHO lab studies which showed that the drug was 99% ineffective against prevalent flu strains (see above). 

12)  Cochrane had also missed the issues of side effects and journal bias.  No mention was made of side effects by Cochrane, though one had caused quite a stir.  As of February 4, 2006, 39 deaths had been associated with oseltamivir in Japan, 13 of which were of children aged 16 and under.5  Several of the deaths in children involved falls from high places.6  In 2008 the FDA and Roche issued an advisory warning regarding neuropsychiatric events associated with the use of oseltamivir.  Most of these reports were from Japan and included delirium and abnormal behavior leading to injury, and in some cases resulting in death”.9  WorstPill.org.  More on this in Wikipedia:  “Roche then did its own study of 2,800 children using a professor of pediatrics at Yokohama University who found no difference in behavior.  But a carefully constructed study by the Japanese Health Ministry found that children who took oseltamivir were 54 percent more likely to exhibit abnormal behaviour than those who did not take the drug”.  What about affecting adults?  The journal articles claim it to affect only children (good damage control by Roche, using their stage iv studies).  What of other side effects?  A http://scholar.google.com/ found none.  This is surprising given its bio activity as a neuramidase inhibitor.  This rare serious side effect gives the appearance of effective government supervision.  The FDA issued a black box warning about risk to children (which appears on the package).  It had little effect upon sales of Tamiflu. 

13)  This side effect was barely mentioned by our PhARMA friendly corporate press.  A Google search found an article by Reuters in 2007.  Moreover in the article they used a statement by Roche denying a causal relation of deaths to Tamiflu.  The article also clearly implied that Tamiflu is effective treatment of the flu.   Under the mountain of positive press the public believes that Tamiflu is effective.  Tamiflu and Relenza (the knock off drug) are aggressively marketed and their sales continue to grow because doctors and the public hear of the drugs perceived benefits; not the ineffectiveness, the need to take the drug within 24 hours of symptoms, and its side effects.  Roche, their thought leaders, treatment protocols, corporate media, and political connections[13] have won the market battle.  Political connections explain why governments continue to be stockpile a drug that is 99% ineffective against the flu (WHO Study above).    

14)  PhARMA should not generate & control the information about their drugs—a conflict of interest.  For example, side effects are always underestimated and only partially known.  The information supplied by thought leaders in continuing education classes & by sales reps is flawed.  Very, very few doctors are inclined to study journals and come to an informed opinion as to the costs-benefits of the drugs they prescribe.  Most journal articles are only available for free[14] on line at a medical college library.  Bias and partial information makes critical evaluation often impossible.  Only for a few drugs are there sufficient studies to arrive at a valid conclusion; and to do so require sifting through hundreds of PhARMA-funded articles and a few by critics.  It takes hundred of hours to arrive out a reasonable conclusion.  Given these issues doctors who practice medicine in a corporate setting conform to the PhARMA set norms. 

15).  Considerable pressure is placed upon physicians to conform.  In hospitals, nursing homes, and clinics, corporate administrators set up treatment protocols.  These administrators receive kick backs from drug-company sales reps for including their drugs in the protocol.  Continued employment is contingent upon following the protocols.  And thanks to direct-to-consumer advertising, most patients expect to be heavily medicated with the latest drugs.  Keeping patients is in part based upon fulfilling their expectations.  And if they don’t follow protocol, and the condition proves resistant to treatment; this could lead to a mal-practice suit.  Given the PhARMA-published studies justifying the normal course of treatment, it would be difficult for the doctor to convince a court that the suit lacks merit.  Also, mavericks are less likely to get referrals from colleagues; or perks from PhARMA.  .  The web protocols weave extends to respected professional societies:  “The guidelines represent the standard of care against which they will be judged in any claims of malpractice”.  The article is on alteplace, and ER drug for strokes which causes a higher death in 10 out of 12 trials.  Without knowing what is best, following the advice of a thought leaders and treatment protocols is the doctor’s prudent choice.          

16)  The power of the gorilla entails “ostrich behavior” from the FDA, journal editors, and medical schools as to side effects, etc.  This ignorance as to drug side effect and effectiveness could cheaply be reversed for there are mountains of long-term data on drugs and side effects, including those not uncovered in the short-term phase III studies.  They reside in the data banks of the HMOs, Kaiser Permanente, Veterans Affairs hospitals, corporate hospitals, Medicare, and nursing homes.  The long-treatment records are not available for inexpensive, scientific analysis.  Costly, long-term phase IV studies don’t fill that gap because PhARMA studies conform to the standards of tobacco science, and FDA sponsored studies are PhARMA friendly.  Moreover their major studies have market objectives including finding new uses, expanding uses, quelling concerns over side effects, showing their drug is safe and effective, and better than older off-patent one[15].  The gorilla is in favor of tobacco sciences and against the use of data banks in an unbiased way.      

17)    Often journal reports of and the media brouhaha over side effects muddle the issues[16].  Tamiflu’s statistical association with a few children deaths is a typical example.  The issue for a treatment is the harm done compared to the benefits.  This requires complete and accurate data.  As stated on page one, the highest standard consists of an active search for side effects and benefits.  This ought to be done by independent, well-funded scientists with a mandate like that of NICE[17] supported by a global organization such as the WHO (World Health Organization).  Raw data must be published.  The research performance should be reviewed by not-for profit, universities which would be involved in choosing areas to research with the goal of benefiting the public.  Many healthful leads and issues that ought to be investigated aren’t because the finical incentives for a corporation to investigate are lacking.  We need health science.

18)  How much harm?  The theme piped in through direct to consumer advertising:  better living through miracle drugs brought to you by big PhARMA, who is supervised by the vigilant FDA that makes PhARMA rattle off a list of side effects at the end of their television commercial. This is ad doesn’t promote informed choice.  How many Americans remember the 2005 media coverage of the greatest known drug disaster, Vioxx?  In the 6 years on the market over 100 million prescriptions and 20 million Americans took Vioxx.  A 2005 estimates place it at 125,000 heart attacks including 55.000 deaths caused by taking long-term the selective COX-2 inhibitor Vioxx.[18]  The preliminary testing for a patent, which is short-term, couldn’t uncover the acceleration of atheriogenesis (hardening of the arties) caused by Vioxx.   The phase I & II study of Vioxx which included 5,000 patients ”the data did not find an increased risk of heart attack or stroke” [it was short-term, younger population].  To rely on PhARMA & the FDA to expose side effects is folly. 

19)  The pattern of folly is revealed in the unintended results for clinical trials and the responses by Merck and the FDA.   Three major studies were funded by Merck for to find new uses & promote Vioxx as superior to the other NSAIDs (Non- Steroidal Anti-Inflammatory Drug).  Older NSAIDs inhibit the COX-1 and COX-2 hormones[19].  A new family, selective NSAIDs, inhibit only COX-2.  Given this difference, Vioxx and its 8 knock-offs were marketed as being a more effective analgesic and causing less adverse gastro-intestinal (GI) events (“these claims have never been convincingly demonstrated”, Goodman & Gilman 11th Ed.).  The 2000 VIGOR (Vioxx GI Outcome Research) study sponsored by Merck compare the efficacy of Vioxx to Naproxen for GI outcomes.  Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, [NEJM] the journal editors learned that certain data reported to the FDA were not included in the NEJM article.  NEJM responded with indignation in their editorial over the deceptive article they published 2 years earlier.  But they knew that withholding information on side effects is the norm because the raw data from the study is never in its entirety submitted.  NEJM protest is thus deceptive. The missing data showed a significant 4-fold increased risk of acute myocardial infarction in rofecoxib [Vioxx] patients when compared with naproxen patients.”  Merck incongruously argued in journals and to the FDA that Vioxx’s didn’t cause the excess deaths from heart attacks, but rather that Naproxen prevent them through its superior thrombolytic function.  But the best drugs at preventing blood clots only reduce heart attacks (MI) about 30%--not 4-fold.  Moreover Naproxen had never been shown to provide this type of cardiovascular protection.  In the 2001 APPROVe study (Adenomatous Polyp PRevention On Vioxx), a three year trial to see if Vioxx would reduce colon polyps: “A total of 25 [elderly] patients receiving placebo and 45 receiving Vioxx demonstrated thromboembolic events…. Including heart attack and stroke appeared statistically evident at 18 months of chronic dosing.”  Two years later these fatal side effects were made public by Merck.  A third study 2000 to 01 to see if Vioxx prevented Alzheimer’s (also using a high risk population) had similar results, and was terminated early.   Merck this time simply sat on the data for 3 years, and then when it decided to withdraw Vioxx from the market, Merck then published the fatal results (2004 and 2005).  The 2005 article revealed 39 deaths in the Vioxx group and 15 in the placebo group. These mortality analyses were neither provided to the FDA nor made public in a timely fashion” JAMA.  Troubling is that the Vioxx disaster was exposed in 2000, the FDA responded with a black-box warning in 2002[20], but it was Merck who in Sept. 2004 after sitting on the results of 2 major trials for 3  years, who voluntarily withdrew its mega-blockbuster, Vioxx.  (With Tamiflu 8 out of 10 studies were not published.)  This pattern is not new.  For example the same occurred with DES, approved by the FDA for birth control in 1942, and subsequent used to prevent in pregnant women spontaneous abortion—though the evidence for this use was far from convincing.  In 1971 it was found to increase vaginal and cervical cancers 40 fold in daughter of mothers given DES.  Soon it was shown to cause several types of internal genital abnormalities in exposed sons and daughters.   Nevertheless it remained available until the in 1997 when Eli Lilly stopped marketing DES.  Merck voluntarily withdrew Vioxx in 2004.   We need enforced regulations requiring the collecting of stats on all side effects and their prompt, unbiased reporting--and major penalties.  And we need an industry unfriendly regulatory agency that will remove promptly such horrors.    

20)  Unfortunately the events surrounding Vioxx as to FDA and Merck’s handling side effects and efficacy is the norm.  It illustrates inadequacies: the FDA’s protection of the public, the accuracy of journal articles, the legal system, and how election-funding affects our legislation.  It illustrates how the worse known drug disaster is quickly forgotten, and its consequence barely punished.  We all know of 9/11, but most have forgotten that over 20 times as many American died from taking Vioxx.  Civil suits were settled for under $1 billion, a fraction of profits.  There were an estimated 160,000 excess heart attacks & 55.000 deaths from 1999 to 2003 among the 20 million users, and more to this day since Vioxx accelerated hardening of the arteries.  It also illustrates the inadequacies of the system for monitoring long-term side effects (more on that later).  Shockingly, Vioxx’s knockoff Celebrex is still heavily advertised, though the FDA’s advisory committee unanimously recommended the prohibition of direct-to-consumer advertising because the evidence showed the same atherogenesis process.[21]  There is no pressing need for the family of selective COX-2 inhibitors, which they belong to.  These drugs have never soundly been shown to afford more pain relief, arthritic protection, or cause less hemorrhaging than the non-selective NSAIDs, though PhARMA of course has produced studies supporting these claims, and the FDA uses these studies to justify the continued approval of Celebrex and 6 others

21)  Illustrative of the effective control of the production of information concerning drugs and their usage and the relentless pursuit of profit maximization is the use of NSAIDs such as Celebrex, naproxen, and ibuprofen.  In the last 2 decades it has come to light that all of the NSAIDs but aspirin—both selective and non-selective COX inhibitors--increase the rate of atherogenesis, and thereby contributes to cardiovascular disease (CVD).  A rough estimate would be for each day on them is equivalent to smoking a pack of cigarettes—there are major difference in rate depending on the NSAID.  This analogy to cigarettes highlights their delayed effect on younger users, its accumulative long-term effect, and the much higher risk for those already with hardening of the arteries.  This is why only an elderly population could expose this side effect within 2 years.  Vioxx and Celebrex were tested for conditions requiring an elderly population such as colon polyps and Alzheimer’s disease.  Testing in the elderly should be required for all drugs.  This acceleration of CVD caused by NSAIDs has resulted in the American Heart association issuing a clear warning--see also journal sources.  For the reasons developed (see #1), this fact of CDV risk has minimal market impact, for PhARMA only sells the fluff.  Moreover, aspirin, the only NSAID not to promote CVD is not recommended for pain, for inflammation, or to prevent blood clots, because of a “perceived” greater risk of GI events.  (And aspirin prevents and increases survival of most common cancers).  Thank you PhARMA and the FDA.         

22)  How serious is the problem (drug interactions, overdoses, side effects)?  Various studies have been performed about medical errors….  The Institute of Medicine (IOM) reports on two studies estimating the hospital deaths due to medical errors at 44,000 to 98,000 annually, which would place medical errors in the top ten causes of death in the USA. Barbara Starfield's article in JAMA places the estimates even higher, citing a total of 225,000 deaths due to iatrogenic causes, which would place health-care deaths as the 3rd leading cause of death in the USA. Holland et al (1997) estimates as many as 1 million patients are injured while in the hospital and approximately 180,000 die as a result, with the majority due to medication adverse reactions”  Doctor Philippe Even, director of the prestigious Necker Institute estimates for France 20,000 death and  100,000 hospital admission--multiple those numbers by five to adjust for the US population.  The number of early death is much higher (see #5 above) because most adverse events are not recognized, and there is no requirement for physician reporting.  This dismal assessment is supported by the 1871 British census:  “males who lived to adulthood averaged 75 years. Present, male life expectancy in the U.K. is 77 years for males” (source Wikipedia “longevity”).   With all the life extending interventions:  cancer, heart attacks, diabetes, kidney stones, trauma, vaccinations, antibiotics, plus healthier working conditions, sanitation, less smoke from fires,  something must be at work to undo this progress.  Two reasons are tobacco and obesity which shorten life an average of 7 and 5 years respectively.  They afflict 25% and 33% of the population thus causing an average deduction of 3 years.  After that the life-long chemical bath (called drugs) shortens on an average lives by 3 years.  Next on the grim list are the corporate farms and food additives—deduct 2 years.  These wipe out male-adult health care gains since the 1871 census. 

23)  In 1970 the medical bill accounted for 5 % of GDP, today it is 17% of GDP.  The main improvement in survival since 1970 has been through the injection of clot busting drug in the emergency room of hospitals for those with heart attack or stroke, and the reduction in tobacco usage[22].  PhARMA in our corporatist state has the highest return on investment of any sector of the economy.[23]  There is a fundamental conflict of interest the public health and maximizing profits.   Though fixes are not on the political horizon, since corporations are the shadow government; a public awareness of the greed & harm done by corporate medicine and the need for a populist government to fix this mess, this is the first step.   Though PhARMA paints a rosy picture,[24] we get very little for the major bump in the cost of health care.

24)  ADVICE on avoiding side effects:  Given the state of corporate medicine, to base an evaluation of a drug on the journal literature is a mine field.  In journals positive results, biomarkers, metastudies, treatment comparisons are all subjected to corporate ethics.   To rely upon a person trained by PhARMA, your physician, is to greatly increase the risk of making the poor choices.  Sincerity is a poor guide.  On the positive side, learn about your condition from medical textbooks such as Conn’s Current Therapy, Merck Manual on line, and Wikipedia.  Let your doctor know that you are not a pill popper.  Watch out for downers (tranquilizers) which have many uses.[25]  Don’t ask for drugs for psychological problems, they are all downers. Mental confusion creates reliance upon your doctor.  Follow worstpills.org[26] recommend:  ask for an older, off-patent alternative drug, because the side effects are more likely to be revealed.  Many of the older drugs have been proven to be more effective, though your doctor has been “taught” otherwise.  Rely upon the advice at http://healthfully.org/rc/. There you will find how and what PhARMA has turned upside down.  More are published every month.  Two examples:  the truth about the effect of hormone replacement therapy for men and women and the protection from cancer through daily usage of aspirin which activates the bodies system for the destruction of abnormal cells.  These and other topics are carefully researched in ways that removes the corporate labyrinth of deceit and arrive at the best-reasoned conclusions based upon the most reliable evidence.  These articles are not faith pitches (trust me I am an expert), but rather evidenced based, with links to journal articles (often older ones).[27]  As Dr. Philippe Even, the author of "The Guide to the 4,000 Useful, Useless or Dangerous Medicines"[28] told The Guardian: “The pharmaceutical industry is the most lucrative, the most cynical and the least ethical of all the industries. It is like an octopus with tentacles that has infiltrated all the decision-making bodies:  world health organizations, government agencies, parliaments, high administrations in health and hospitals and the medical profession." My 10 years of developing the website http://healthfully.org has confirmed that summation. You should take better care of your health than your car.  And remember the warning by Dr. Ben Goldacre in Bad PhARMA, page xv:  “Doctors spend forty years practicing medicine with very little formal education after their initial training.  Medicine changes completely in four decades, and as they try to keep up, doctors are bombarded with information:  from ads that misrepresent the benefits and risk of new medicines; from sales reps who spy on patients’ confidential prescribing records; from colleagues who are quietly paid by drug companies; from ‘teaching’ that is sponsored by industry; from independent ‘academic’ journals articles that are quietly written by drug company employees; and worse”

Worse includes treatment protocols that are generated by friends of PhARMA. Below is an article from the British Medical Journal, June 2013 that provides insight into the power of PhARMA and its close ties with professional organizations, in particular the Congress of Neurological Surgeons and the US National Institute of Health (NHI). 

[1] PhARMA, Pharmaceutical Association Manufacturers Associations.   I, and others, use “Big PhARMA” to stand for the industry. 

[2] Lowering the standards for prescribing by PhARMA sponsored (cooked) studies occurred with statins—so too for increasing the dosage.  This pattern of ‘marketing science”, because it is ignored by the FDA, is an industry norm.  Sales reps & thought leaders have a free-speech right to recommend off-label usages of drugs, and such usage account for over 50% of sales for most drugs.  

[3]  Since PhARMA pushes statins as well tolerated; its lowering the production of CoQ10 by 40% is not mentioned by their thought leaders.  CoQ10 is essential for the production of ATP, the body’s energy source for active transport, chemical reaction including for muscle contractions (the heart is a muscle), and much more.  This is why elite athletes don’t tolerate statins--see 2 above.  This reduction explains the varied side effect from statins.  Secondly, if mentioned it would be counter indicated for those over the age of  70 and also those with congestive heart failure because the reduction in CoQ10 significantly increases deaths from heart attacks among the weak.   Several journal articles state that the failure to disseminate this knowledge & promote the use of CoQ10 as tragic.    

[4] 800 pound gorilla a term used by Professor Marcia Angell to describe PhARMA in her book The Truth about Drug Companies.

[5] Thought leaders are renowned specialists.  They rise to prominence thought providing services for PhARMA, for which most receive 6-digit income. Their success is dependent upon being PhARMA “friendly”. They are university department and organization heads, researchers, and authors.  Thought leaders lecture at continuing educational classes for doctors, and they are interviewed by the media.  They are part of the chorus that pushes drugs as safe and effective.  

[6] Raw data: includes experiment’s protocol, patient’s results, methods, interim results, conditions, etc.  collected during the study. 

[7]  Phase I safety study, first on animal than on a 20-100 humans.  Phase II on efficacy and dose on typically 100 to 300 subjects. 

[8]  PhARMA, e.g., has done studies to contradict early works that clearly demonstrates the benefits of aspirin, estrogen/HRT, and testosterone.  An incredible amount of harm has been done by PhARMA.  JK takes daily 325 mgs of aspirin and topical testosterone.

[9]  PhARMA, e.g., has done studies to contradict early works that clearly demonstrates the benefits of aspirin, estrogen/HRT, and testosterone.  An incredible amount of harm has been done by PhARMA.  JK takes daily 325 mgs of aspirin and topical testosterone.

[10]  Interpretation:  These data indicate that patients with coronary heart disease and metabolic syndrome derive incremental benefit from high-dose atorvastatin [Lipitor] therapy, irrespective of the presence of diabetes.”  Given that sufficient information on the study was in their hands (BMJ quotation above), the Lancet has hit its low point. The BMJ article (2006) also pointed the failure to reveal side effects which has been repeatedly shown to increase with dosage:However, overall mortality was not reduced because the smaller number of cardiovascular deaths in the 80 mg atorvastatin.”  Moreover, the TNT study failed to list all causes of death in the Lancet article.  

[11]   While Marcia Angell and others write of marketing science and the façade, but only Drs. Even & Debre in Guide Des 4,000 Medicaments (Sept 2012)  address this failure to supply the raw data and the perfunctory  editorial review by medical journals.  

[12]  Their major issues uncovered:  When the team compared published data with the more complete unpublished trial records, they found apparent inaccuracies in the published record of the trials. For example, while unpublished trial reports mentioned serious adverse events (some even classified as possibly related to oseltamivir), one of the two most cited publications makes no mention of such effects, and the other states, “there were no drug-related serious adverse events…. Having pieced together information from more than 16,000 pages of clinical trial data and documents used in the process of licensing oseltamivir, the Cochrane team raises critical questions about how well the drug works, as well as about its reported safety profile. While the drug did reduce the time to first alleviation of symptoms by an average of 21 hours, it did not reduce the number of people who went on to need hospital treatment.”  Given that bias is norm in journal articles (32% positive bias, see # 6 above), the evidence for Tamiflu being more effective than a placebo for approval by the FDA & European regulatory agencies must have been thinner than the journal article which found a reduction of 21 hours for symptoms of the flu.  Why was this drug stockpiled for avian flu?, Twenty –one hours won’t have much effect upon the death rate considering that WHO testing found that 99% of common virus strains are resistant.  

[13]   Politically well connected:  Donald Rumsfeld served as chairman from 1997 until he became U.S. Secretary of Defense in 2001; former Secretary of State George Shultz and the wife of former California Governor Pete Wilson serve on the board [48]Wikipedia.

[14]   A $7 billion industry has evolved.  Corporations have bought up science journals and sells access per article at $39.  Universities spend millions making journal available in libraries, students, and professors.  The inconvenience of access is one more reason why doctors are forced to rely upon thought leaders and sales reps for treatment information.      

[15]  When sponsored by the FDA, it is often designed to promote patented drug sales as has occurred with the WHI study which *knowingly used the worst form of HRT (Prempro) to generalize the results to all other formulations with dire consequences.  

[16]   The deceptive expression of grave concern over a rare serious event is used to hide their bias:  The FDA issues a black box warning, and the media a 2-minute, human interest account.   If the FDA served the public Tamiflu would not have been approved.

[17] The National Institute for Health and Clinical Excellence (NICE) is a special health authority of the English National Health Service (NHS), NICE publishes guidelines in three areas. The use of health technologies…, clinical practice …, and guidance for public sector workers on Health promotion and ill-health avoidance.[4] These appraisals are based primarily on evaluations of efficacy and cost-effectiveness in various circumstances.” Wikipedia.    Unfortunately politicians have turned NICE into a façade, like the U.S.  NIH. 

[18]   The death rate from MI is 44% thus yielding 55,000 deaths from the 125,000 heart attacks. 

[19] NSAIDs are a class of drugs that provide analgesic and antipyretic (fever-reducing) effects, and, in higher doses, anti-inflammatory effects.  Cyclooxygenases have two main isoforms that are called COX-1 and COX-2 (as well as a COX-3). COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system.

[20]  A rather useless act that forces a warning to be placed upon the product, yet has minimal effect upon sales.  For example the heavily advertised Celebrex has a black-box warning, yet its sales continues to grow.

[21]  “There were 29 observational studies uncovering Vioxx use is associated with a significant increase in the relative risk of myocardial infarction…. Why clinical investigators studying Vioxx did not do more to raise concern is a fair question that needs to be answered….  Horton never mentions the culpability of the medical journals.  Concerns over the toxicity of rofecoxib were first articulated in 2000.4 However, a review of the 1032 publications on rofecoxib cited in PubMed reveals that, before Merck withdrew the drug, only a handful of articles raised concerns about its efficacy.” 

[22]  For those ages 65, the deaths from heart attacks fell 30.3% and strokes 36.3% due to injections (before the use of statins).

[23]   Estimates on return run over 14% return.  The six biggest U.S. drugmakers avoided paying $7.05 billion in U.S. taxes last year by shifting their profits overseas.” Bloomberg 3/11/13.  “For years, multinationals such as Pfizer Inc. (PFE), Merck & Co. (MRK) and Johnson & Johnson (JNJ) have been moving ownership of patents and trademarks to subsidiaries in low- or no-tax countries. This has allowed drug companies, as well as businesses in several other industries, to skirt paying U.S. taxes on sales of those products unless the money is returned home.”  Moreover, over 85% of U.S. prescription drugs are imported, mainly from China and India.     

[24]   One more BS from PhARMA which has been masterfully described by Marcia Angell’s The Truth About Drug Companies chapters 2-6.  In those chapters she shows that approximately 10% of innovative drugs are based on research done by Big PhARMA.  That most of Big PhARMA’s research is for marketing (phase iv studies) to extend patent life, to market me-too drugs, and such.  The 90% of innovated research for new types of drugs are funded by NIH, or done by Small PhARMAs, who sells the rights to Big PhARMA.  Small companies lack the army of thought leaders and sales reps to push their innovative product, and many of them can’t afford approximately $30 million needed for a phase iii study for FDA approval.    

[25] Muscle relaxants, rhinitis, anti nausea, blood pressure, etc.  Any drug which is supposed to change psychologically the way you feel is very likely a downer.  Downers have psychological side effects such as drowsiness, vertigo, anger, suicidal thoughts, euphoria, etc.  A drug should not affect behavior unless it is a downer.  A sleeping patient has less muscle spasms, migraines, anger, nausea (for FAD approval and off-label sales). The patient is easier to manage in a nursing home or hospital.  Stimulants are rarely given.   And don’t drug your children for ADHD; there are other ways relieve boredom & relax such as running, sports,  and better schools.          

[26]  Worst Pill is a valuable resource that red-flags many dangerous drugs s.  However, it all too often accepts marketing science attacks upon off patent drugs, and other gorilla antics.  

[27] The older remedies by going off patent do not become less effective—though PhARMA wants us to believe so.  The published science behind the older remedies is often superior, for in the 1970’s and earlier.  PhARMA generally didn’t back then own the results of trials or establish its parameters.  The majority of research was back then done through medical colleges, and PhARMA merely funded the studies.  Thank you neoliberals (globalizers)--starting with the Reagan administration--for fixing the system. 

[28]   The book was published in French in September of 2012, and as of April of 2013 it hasn’t been translated. 

Side effects outline


1.   Introduction, problem profit maximization versus public safety

2.  Safe and effective, example of 22 elite athletes on statins, not tolerated standard, expanded & new uses. 

3.  Major medical event, Warfarin counting only 2 or more pints of blood.

4.  Self-reporting low standard, Ideal is an active search for side effects by independent scientists. 

5.  Roche sitting on physicians reports of side effects rather than assessing them and forwarding them to the EMA and EMA to the FDA’s AERS system.  Reports are voluntary for doctors, and thus under reported. 

6.  Phase III studies, better than a placebo, raw data submitted to FDA, but FDA does not review journals articles based on raw data Phase iii.  Gap of 32% between raw data in Phase III studies and bias in journal articles. 

7.  Phase IV designed by marketing for promotion of sales (extend patents, prove safety, new uses, higher doses, superiority, seeding use, below standards of phase III.  Sales reps and thought leaders use the results.

EXAMPLES hiding side effects:

8.  Selling benefits, Lipitor world biggest block buster, stats on usage of statins

9. TNT study statins expands the category for treatment, exclusion of those in study, of those once treatment started.  Example of unreliable studies and journal articles.

10.  Meta-study, a stew of marketing science journal articles. 

11.  Tamiflu blockbuster flu treatment, unpublished clinical trials, flu virus resistant to Tamiflu, lack of positive effects, side effects, not delivering raw data as agreed to Cochrane. 

12.  Abnormal behavior in children and 39 deaths in Japan after Tamiflu, and black-box-warning.

13.  Silence in press over death in children, and positive spin by Router’s article. 

14.  PhARMA’s control of information and arriving at reasonable conclusion on the few sufficiently research topics.  Doctors in corporate setting conform to PhARMA set norms.   

15.  Pressures upon doctors to conform to treatment protocols. 

16.  Ostrich behavior, tobacco since and the failure to use available data banks of hospitals, nursing homes, Medicare etc.  to reveal side effects and effectiveness. 

17.  Brouhaha over rare serious side effects creates an illusion of FDA protecting public and media not being bias.  Need for a body like NICE to evaluate treatments.

18.  How much harm is done? Vioxx example.

19.  Vioxx studies and asleep at the wheel; DES asleep at the wheel.

20.  Lessons learnt from Vioxx disaster.

21.  No need for COX-2 inhibitors, NSAIDs causing CVD, superiority of aspirin. 

22).   How serious is the problems?  Drug error deaths, side effects deaths, British census of 1871, and 2 year gain in life for  mature males compared to now, reasons, obesity, tobacco, drugs, corporate farms and food additives. 

23.  Improvement in survival since 1970 has been based on injection of clot busting drug for MIs and strokes, and reduction in cigarette smoking.

24.  Advice, don’t be a pill popper, many older off-patent drugs are safer and more effective, go towww.worstpills.org and http://healthfully.org/rc/index.htm, and live healthfully.  Be a skeptic and remember “the pharmaceutical industry is the most lucrative, the most cynical and the least ethical of all the industries. It is like an octopus with tentacles that has infiltrated all the decision-making bodies:  world health organizations, government agencies, parliaments, high administrations in health and hospitals and the medical profession."



There is an ever growing revulsion by physicians over the corporate takeover.   Four weeks before this, BMJ publish an article by a physician who was invited by a collogue to be part of an advisory panel.  He describes how at the beginning of the meeting, without discussion of the matter before them, the panel voted to approve the new protocol.  A panel of PhARMA friendly physician will not review a protocol in the public’s interest.  Below is one more example of how business is done.  This article points out that the fear of malpractice suit compels physicians to follow protocols--jk. 


Evidence Based Medicine

Why we can’t trust clinical guidelines

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3830 (Published 14 June 2013).  Cite this as: BMJ 2013;346:f3830 

Jeanne Lenzer, medical investigative journalist            jeanne.lenzer@gmail.com


Despite repeated calls to prohibit or limit conflicts of interests among authors and sponsors of clinical guidelines, the problem persists. Jeanne Lenzer investigates

On 13 April 1990, in an unprecedented action, the US National Institutes of Health faxed a letter to every physician in the US on how to correctly prescribe a breakthrough treatment for acute spinal cord injury. Many neurosurgeons were sceptical of the evidence that lay behind the new recommendation to give high dose steroids, yet when two respected organisations released a review and a guideline recommending the treatment, they felt obliged to give it. Now, over two decades later, new guidelines warn against the serious harms of high dose steroids. This case and others like it point to the ethical difficulties that doctors face when biased guidelines are promoted and raise the question: why do processes intended to prevent or reduce bias fail?

Doctors who are sceptical about the scientific basis of clinical guidelines have two choices: they can follow guidelines even though they suspect doing so will cause harm, or they can ignore them and do what they believe is right for their patients, thereby risking professional censure and possibly jeopardising their careers.1 2 34 This is no mere theoretical dilemma; there is evidence that even when doctors believe a guideline is likely to be harmful and compromised by bias, a substantial number follow it.5

Disturbing precedent

In the early 1990s, high dose steroids became the standard of care for acute spinal cord injury,6 reinforced by a Cochrane review. The Cochrane Collaboration, is widely known to have strict standards concerning conflicts of interest, yet in this case the collaboration permitted Michael Bracken, who declared he was an occasional consultant to steroid manufacturers Pharmacia and Upjohn, to serve as the sole reviewer.7 He was also the lead researcher on the single landmark study, published in the New England Journal of Medicine,8 used to support the Cochrane review. 

Neurosurgeons were not convinced. Many expressed concern about high rates of infection, prolonged hospital stays, and death with high dose steroids.9 10 One expert estimated that more patients had been killed by the treatment in the past decade than died in the 9/11 World Trade Center attacks.5

A poll of over 1000 neurosurgeons showed that only 11% believed the treatment was safe and effective. Only 6% thought it should be a standard of care. Yet when asked if they would continue prescribing the treatment, 60% said that they would. Many cited a fear of malpractice if they failed to follow “a standard of care.”5

That standard was reversed this March, when the Congress of Neurological Surgeons issued new guidelines. The congress found that, “There is no Class I or Class II medicine evidence supporting the benefit of [steroids] in the treatment of acute [spinal cord injury]. However, Class I, II, and III evidence exists that high-dose steroids are associated with harmful side effects including death.”11

Manufacturing consensus

Guidelines are usually issued by large panels of authors representing specialty and other professional organisations. While it might seem difficult to bias a guideline with so many experts participating under the sponsorship of large professional bodies, a worrying number of cases suggests that it may be common.

A recent survey found that 71% of chairs of clinical policy committees and 90.5% of co-chairs had financial conflicts.12 Such conflicts can have a strong impact: FDA advisers reviewing the safety record of the progestogen drospirenone voted that the drug’s benefits outweighed any risks. However, a substantial number of the advisers had ties to the manufacturer and if their votes had been excluded the decision would have been reversed.13 [Used in birth control pills, Drospirenone causes a 6 fold increase in blood clot—the most common serious side effect of birth control pills.]

Biased guidelines can have powerful and wide ranging effects. Thousands of guidelines have been issued,14 and, when promulgated by highly respected professional societies, they sometimes serve as de facto “standards of care” that may be used to devise institutional protocols, to develop measures of physician performance, and for insurance coverage decisions. Guidelines may influence the medicines selected for inclusion on drug formularies and may be used as a “reliable authority” to support expert testimony in malpractice suits.4 Eighty four per cent of doctors say they are concerned about industry influence over clinical guidelines,12 yet the fear of malpractice suits puts many in an untenable position of following guidelines they believe are flawed or dangerous to patients.

Despite repeated calls to prohibit or limit conflicts of interests among guideline authors15 16 and their sponsors, most guideline panellists have conflicts,17making the guidelines they issue less than reliable.

Exuberant claims for alteplase in stroke

A similar scenario may be playing out for the use of the thrombolytic drug alteplase in acute stroke. Earlier this year, the American College of Emergency Physicians with the American Academy of Neurology (jointly)18 and the American Heart Association,19 separately, issued grade A level of evidence guidelines for alteplase in acute stroke. The simultaneous recommendation by three respected professional societies would seem to indicate overwhelming support for the treatment and consistent evidence. However, an online poll of 548 emergency physicians showed that only 16% support the new guidelines.20 Although the poll was not scientific, other surveys show substantial scepticism among emergency physicians and the treatment remains contentious.21 22 23 24 25 26 27

Guideline authors say that opposition to the guidelines is insubstantial. Andy Jagoda, a member of the guideline committee and professor and chair of emergency medicine at Mount Sinai School of Medicine, said that “almost all” resident physicians “believe in tPA [alteplase] for stroke.” Another guideline author, Steven R Messe, assistant professor of neurology at the Hospital of the University of Pennsylvania and the Pennsylvania Hospital, told the BMJ that “only a small, vocal minority [of emergency physicians] are opposed.”

An earlier survey claimed that emergency physicians don’t oppose alteplase for stroke. At a glance, the claim seemed justified: the poll found that 83% of the doctors surveyed said they would give the treatment.21 However, when asked whether “the science supports the use of tPA [alteplase],” only 49% agreed.

Alteplase was approved for acute stroke after the 1995 National Institutes of Neurologic Diseases and Stroke (NINDS) trial showed a 13% absolute reduction in disability.28 Advocates quickly began to promote the treatment with exuberant claims. The American Heart Association said it could “save lives,” a claim the organisation was forced to withdraw in 2002 when it was pointed out that no study had shown a mortality benefit.29 In 2007, leading stroke experts with industry ties repeated the “saves lives” claim in the New York Times, suggesting that far too few stroke patients were receiving the drug, largely because of resistance among emergency physicians. The newspaper later published a brief correction stating there was no evidence to support the claim that the drug saved lives.30

But as with steroids for acute spinal cord injury, claims of benefit rest on science that is contested. Sceptics say that baseline imbalances, the use of subset analyses, and chance alone could account for the claimed benefit.24 26 31 32 33 They also note that only two of 12 randomised controlled trials of thrombolytics have shown benefit and five had to be terminated early because of lack of benefit, higher mortality, and significant increases in brain haemorrhage.33

In addition, the guideline committee did not include the largest study of the treatment to date in its analysis. Messe, who was one of the guideline’s authors and a spokesperson until April 2011 for Boehringer Ingelheim, Genentech’s European marketing partner, told the BMJ that the joint panel did not include the International Stroke Treatment-3 (IST-3) Trial because the outcome “showed a benefit” among subgroups and because the patients treated were not the same population as in the NINDS trial. However, the effect on the primary outcome in IST-3 (treatment of stroke from 0-6 hours) was actually negative, and the claimed benefits were based on secondary, exploratory analyses. When this was pointed out, Messe acknowledged that the primary outcome was negative and said, “No one has claimed, nor do we recommend, treatment up to 6 hours.”

The new grade A recommendation by the American College of Emergency Physicians is seen as particularly surprising because emergency physicians have been the strongest critics of the treatment. In a survey of 1105 emergency doctors, 40% said they were “not likely to use” alteplase for acute stroke even under the ideal conditions recommended by the NINDS protocol.34 Two thirds of those doctors cited the risk of symptomatic intracerebral haemorrhage as the factor that most concerned them. A quarter cited the lack of clear treatment benefit.34 Their concerns seem understandable in light of a Cochrane review of pooled effects that showed alteplase increased fatal intracerebral haemorrhage nearly fourfold, and that thrombolytics overall were associated with a significant increase in mortality by the end of follow-up, representing an extra 30 deaths per 1000 treated patients.35

Curt Furberg, a prominent methodologist and former Food and Drug Administration adviser, told the BMJ: “The most powerful evidence comes from the Cochrane pooled analysis.” Furberg objected to the use of subgroup analyses to prove benefit, saying, “When clinical trial results are heterogeneous, it’s important to look at the totality of evidence. You should never draw firm conclusions from post hoc analyses. You can’t just select data that supports the thesis you like by asking, ‘How do the results look at 2 hours? How about 2 hours and 10 minutes? How about 3 hours?’ By chance alone you will find something that supports your bias.”

Best guidelines influence can buy: how it happens

Proponents of alteplase have launched projects to ensure uptake of the guidelines in the US, such as the development of “stroke certified hospitals,” which require hospitals to commit resources to enable rapid administration of alteplase to eligible stroke patients. Since ambulances divert patients with suggestive symptoms to stroke certified hospitals, the project has substantial financial ramifications. These efforts, and others like the “Brain Attack” campaign, have been actively supported by the American Heart Association and American Stroke Association, which “partnered” with the Joint Commission (a quasi-governmental agency that accredits hospitals) to promote hospital stroke certification. Genentech, Boehringer Ingelheim and Novo Nordisk, which market alteplase, have contributed tens of millions of dollars to the associations.

In its newly released guidelines, the American Heart Association states that it “makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of . . . a business interest of a member of the writing panel.” However, according to their conflict of interest disclosure statements, 13 of the 15 authors had ties to the manufacturers of products to diagnose and treat acute stroke; 11 had ties to companies that market alteplase.19 In 2010, two years after the association launched this guideline panel, it revised its financial conflicts policy; in the future, neither committee chairs nor the majority of its guideline writing members may have any relevant ties to industry.

Concern about the credibility of guidelines led the Institute of Medicine to recommend that ideally no guideline authors should have financial conflicts of interest.14 If individuals who have professional conflicts that can’t be divested (for example, specialists whose career depends on treating a certain condition) are included, the institute recommends that they “should represent not more than a minority” of the panellists.14  [Such requirements by the professional organizations is mere window dressing, for business continues as before, there hasn’t been a flock of changes in protocols.]

In the guidelines issued jointly by the American College of Emergency Physicians and the American Academy of Neurology, three of eight panellists disclosed ties to the manufacturers. However, seven had either direct ties to the manufacturer or indirect ties, knowingly or not, through affiliations with the Foundation for Education and Research in Neurological Emergencies (FERNE), which provides unrestricted continuing medical education grants (table). Guideline readers were unlikely to know that according to its 2008 tax return, 100% of the $97 000 donated to the foundation that year came from drug companies, including $50 000 from Genentech. The foundation president and founder, Edward P Sloan, is an outspoken advocate of alteplase for stroke.36


Competing interests of authors of American College of Emergency Physicians and the American Academy of Neurology guidelines on alteplase


Competing interest











Boehringer Ingelheim



Boehringer Ingelheim



FERNE only


Speaker for FERNE* (not stroke related)



Adviser and speaker for FERNE*



For all guidelines, the overwhelming majority of committee chairs and cochairs have ties to industry,12 and selection of panellists with desired viewpoints can make a wished for outcome a foregone conclusion. Committee stacking may be one of the most powerful and important tools to achieve a desired outcome. Seven of the eight panellists had previously published or lectured on the merits of alteplase for stroke. The eighth panellist, Robert Wears, described himself as an “agnostic” but added that he was “surprised” that he was named as an author since he had resigned from the committee six years earlier. Not one sceptic was included on the panel. In response to a question about whether any known sceptics were invited to be on the committee, a spokesperson for the American Academy of Neurology said, “A potential panel member’s opinion on a topic does not determine eligibility for participation on an American Academy of Neurology guideline author panel. The guideline development process is evidence based.”

Wears, a highly respected methodologist and professor of emergency medicine at the University of Florida Health Sciences Center, had been the methodologist for the committee. He told the BMJ that he resigned in part because he was growing increasingly “disillusioned” with the guideline process. When asked why Wears’ name appeared as one of the committee members, Rhonda Whitson, clinical practice manager for the college told the BMJ, “He may have thought his role on the tPA panel ended sooner than it did . . . However, he did participate throughout the project as needed for his role.”

A spokesperson for the Annals of Emergency Medicine, which published the clinical policy, explained how Wears’ name was able to appear in the journal. She told theBMJ that it does not peer review the college’s clinical policies; nor does it vet the authors or members of the development panel.

Widespread problem

Many other conflicted guidelines have come to light in recent years. In 2006, the New England Journal of Medicine published an article warning against aggressive treatment of anaemia with erythropoietin in patients with kidney disease. Patients treated aggressively had increased rates of heart failure and need for dialysis.37Yet guidelines issued in 2007 by the National Kidney Foundation, which received multimillion dollar donations from companies that make erythropoietin, recommended aggressive treatment that would increase the number of patients receiving the drug.38

In 2004, newly issued cholesterol guidelines greatly expanded the number of people for whom treatment is recommended. A firestorm broke out when it was learnt that all but one of the guideline authors had ties to the manufacturers of cholesterol lowering drugs.39

Yet these and other guidelines continue to be followed despite concerns about bias, because as one lecturer told a meeting on geriatric care in the Virgin Islands earlier this year, “We like to stick within the standard of care, because when the shit hits the fan we all want to be able to say we were just doing what everyone else is doing—even if what everyone else is doing isn’t very good.”


Cite this as: BMJ 2013;346:f3830


·         Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.

·         Provenance and peer review: Commissioned; not externally peer reviewed.


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