How Many Straws? - Johnson and Johnson Settles Again, Again, Again...

It seems like a minor case, but is another straw for the camel. <br /><br /><b>The Latest Settlement </b><br /><br /><a href="http://www.modernhealthcare.com/article/20131205/NEWS/312059936/two-jj-executives-agree-to-50000-in-fines-over-mislabeled-products">Reported</a> in most detail by Modern Healthcare, <br /><br /><blockquote class="tr_bq"><i>Two executives at a subsidiary of Johnson & Johnson have agreed to pay a total of $50,000 to resolve allegations that they knowingly sold mislabeled products used in the sterilization of gastrointestinal scopes and surgical drills.  The settlement also calls for the J&J subsidiary, Advanced Sterilization Products, to pay $1.25 million to resolve a civil complaint filed by the Food and Drug Administration. ASP President Bernard Zovighian will pay $30,000, while Richard Alberti, quality and compliance vice president, will pay $20,000. None admitted wrongdoing.</i><br /><br />'ASP's actions violated the law and put patients at unnecessary risk for infection,' Steve Silberman, director of compliance at the FDA Center for Devices and Radiological Health, said in a statement.<br /><br />Last year, ASP announced two recalls affecting a product called the Cyclesure 24 Biological Indicator, which is used to make sure that medical equipment sterilized using ASP's Sterrad low-temperature cleaning machines is free of bacteria, fungi and viruses. <br /><br />FDA inspectors, according to a civil complaint last July, uncovered evidence that the company sold the Cyclesure 24 tests with 15-month expiration dates even though ASP's internal studies had not established the product's safe shelf life was that long. <br /><br />After the issue was discovered, ASP shortened the shelf life of the Cyclesure indicators to six months. The company also recalled all lots of the products manufactured between February 2008 and December 2011. <br /><br />Dirty endoscopes used during colon cancer screenings, for example, have been implicated in the transmission of hepatitis C and many types of bacteria, according to ASP's own website. </blockquote>Note that this case involves not just legal technicalities, but failures of disclosure that could have put real patients at risk of significant harm.<br /><br /><b>The Context </b><br /><br />This case comes only one week after we <a href="http://hcrenewal.blogspot.com/2013/11/there-they-go-again-again-johnson-and.html">discussed</a> a huge ($2.5 billion) settlement by Johnson and Johnson of allegations that it withheld data about major safety problems affecting metal-on-metal hip prostheses, and two smaller settlements of allegations that it withheld safety data about the drug Topamax.<br /><br /><br />It is noteworthy that in this much smaller current settlement, two admittedly relatively low-level executives had to pay fines amounting to 4% of what the company had to pay. This is unusual.  Usually corporate executives escape any negative consequences, even in cases involving large amounts of money or possible harm to many patients.  If last week's settlement were to have imposed proportionate fines on executives, those fines would have totaled $100 million<br /><br />The latest settlement does seem to follow the usual pattern: relatively small time individual offenders pay a penalty, while very rich and powerful individual offenders avoid all penalties. (For example, look <a href="http://hcrenewal.blogspot.com/2013/01/the-tragic-case-of-aaron-swartz-unequal.html">here</a> to see how one US prosecutor handled the case of Aaron Swartz versus the cases of misdeeds by big corporations)   <a href="http://hcrenewal.blogspot.com/search/label/impunity">Impunity</a> by rich and powerful leaders of big organizations, and failure to enforce laws broken by such people is a very old story in American history, but that pattern was interrupted briefly after the great depression through the 1970s.  Now impunity for the rich and powerful is back, and maybe that is why 43% of the American population think our health care system is corrupt (look <a href="http://hcrenewal.blogspot.com/2013/07/43-believe-that-us-health-care-corrupt.html">here</a>).<br /><br /><br />Of course, the current settlement involved no admissions of wrongdoing.  Like most <a href="http://hcrenewal.blogspot.com/search/label/legal%20settlements">legal actions against big health care organizations</a>, it is thus paradoxical.  Fines are paid, but at least on paper, not because of any wrongdoing.  So what were the penalties for?  Who knows?  But allowing a settlement without an admission of wrongdoing allows the next settlement to be made as if it were dealing with an isolated problem.  <br /><br />As we mentioned in our <a href="http://hcrenewal.blogspot.com/2013/11/there-they-go-again-again-johnson-and.html">last post</a> on Johnson and Johnson, the latest settlement should be added to an increasingly  long list of the company's legal woes, often involving allegations and evidence of other unethical actions, sometimes involving guilty pleas to charges of such actions (see compilation of the record through July, 2013 <a href="http://hcrenewal.blogspot.com/2013/07/johnson-and-johnson-settles-suit.html">here</a>.)  Yet each settlement or action seems to take place in a vacuum, with no attention to what appears to be the company's record of ethical recidivism.  Of course, since nearly every action eschewed admissions of wrongdoing, on paper, there was no legal record of recidivism.  The whole situation is becoming so absurd that Jon Stewart on the Daily Show <a href="http://www.thewrap.com/daily-show-jon-stewart-johnson-grand-theft-auto">parodied</a> the ability of Johnson and Johnson, and other big corporations, to escape any meaningful negative consequences of their actions.<br /><br /><br /><div style="background-color: black; width: 368px;"><div style="padding: 4px;"><iframe frameborder="0" height="293" src="http://media.mtvnservices.com/embed/mgid:cms:video:thedailyshow.com:430976" width="360"></iframe><br /><div style="background-color: white; font-family: Arial, Helvetica, sans-serif; font-size: 12px; margin-bottom: 0px; margin-top: 4px; padding: 4px; text-align: left;"><b>The Daily Show</b> <br />Get More: <a href="http://www.thedailyshow.com/full-episodes/">Daily Show Full Episodes</a>,<a href="http://www.facebook.com/thedailyshow">The Daily Show on Facebook</a></div></div></div><br />As quoted on the Wrap<br /><br /><blockquote class="tr_bq">'Holy sh**t. They knowingly bribed doctors to give useless drugs to old people, the disabled and babies,' a stunned Stewart said. 'You’re not even allowed to do that in ‘Grand Theft Auto.''</blockquote><br />When these issues start becoming subjects of popular parody, maybe I can entertain a tiny hope that something might be done. <br /><br /><b> Conclusion</b><br /><br />So I get to say again, again again...  many of largest and once proud health care organizations now have recent records of repeated, egregious ethical lapses. Not only have their leaders have nearly all avoided penalties, but they have become extremely rich while their companies have so misbehaved. <br /><br />These leaders seem to have become like nobility, able to extract money from lesser folk, while remaining entirely unaccountable for bad results of their reigns. We can see from this case that health care organizations' leadership's nobility overlaps with the supposed "royalty" of the leaders of big financial firms, none of whom have gone to jail after the global financial collapse, great recession, and ongoing international financial disaster (look <a href="http://hcrenewal.blogspot.com/2012/08/duchess-of-wellpoint-abdicates-likely.html">here</a>). The current fashion of punishing behavior within health care organization with fines and agreements to behave better in the future appears to be more law enforcement theatre than serious deterrent.  As Massachusetts Governor Deval Patrick exhorted his fellow Democrats, I exhort state, federal (and international, for that  matter) law enforcement to "<a href="http://www.washingtonpost.com/blogs/election-2012/wp/2012/09/04/patrick-it-is-time-for-democrats-to-grow-a-backbone/">grow a backbone</a>" and go after the people who were responsible for and most profited from the ongoing ethical debacle in health care.<br /><br />As we have said before, true health care reform would make leaders of health care organization accountable for their organizations' bad behavior.<br /><br />Roy M. Poses MD on Health Care Renewal  <br /><br />

How Many Straws? - Johnson and Johnson Settles Again, Again, Again...

It seems like a minor case, but is another straw for the camel. The Latest Settlement Reported in most detail by Modern Healthcare, Two executives at a subsidiary of Johnson & Johnson have agreed to p…

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EHR Pastel Madness: Cognitive Overload in Critical Care

It's hard to find public postings that show the crazy and dangerous complexity of EHR interfaces, but I found a presentation at <a href="http://www.uiowa.edu/~medtest2/picis/vo_picis.pdf">http://www.uiowa.edu/~medtest2/picis/vo_picis.pdf</a> (PDF slide presentation) that demonstrates ths problem well.<br /><br />These are from a 2006 training presentation on an EHR for Critical Care , where doctors and nurses really don't have the time to wade through complexity like this.  <b> </b><br /><br /><b>I can honestly and in fact, with great vigor, opine I would not have wanted to use a tool like this when I was working in intensive care units. </b> And I'm a Medical Informatics specialist x 21 years...<b><br /></b><br /><br />EHRs have not changed much; in fact with the higher commodity (cheap) screen resolutions available in 2013 compared to 2006, the problem is worse.<br /><br />Some sample screens:<br /><br /><br /><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgfO5PiBGHM6PxLTm0BkbVqrkXphnnhSJKEMbHJ5bXFDxSzOOsc7nQJgPeaQyB_ZEzV_9tb8I4VMAqYdLN60hctlB3YShdjrEiLakNehhFoxCp8qcHniZhdyg8LPMshtw29EZDXcCmGIG4-/s1600/screen1.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgfO5PiBGHM6PxLTm0BkbVqrkXphnnhSJKEMbHJ5bXFDxSzOOsc7nQJgPeaQyB_ZEzV_9tb8I4VMAqYdLN60hctlB3YShdjrEiLakNehhFoxCp8qcHniZhdyg8LPMshtw29EZDXcCmGIG4-/s320/screen1.jpg" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Click to enlarge</td></tr></tbody></table><br /><br /><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgm0j77Npta-H0BPqMFVaJyiU_g2TeoPpe9ROw-xBjhDg3y8-XZxpbDn2urD1ZsMNU62slKN5U0ZzCKiG1HCd-XNgc5UJ6GLb_V7gu-H4Lj-2NuCxfP4xI2lm5kYqYPEiEGOfbiwKCVhXZW/s1600/screen2.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="238" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgm0j77Npta-H0BPqMFVaJyiU_g2TeoPpe9ROw-xBjhDg3y8-XZxpbDn2urD1ZsMNU62slKN5U0ZzCKiG1HCd-XNgc5UJ6GLb_V7gu-H4Lj-2NuCxfP4xI2lm5kYqYPEiEGOfbiwKCVhXZW/s320/screen2.jpg" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Click to enlarge</td></tr></tbody></table><br /><br /><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0B9MFJCQuhlSHk7ziTNTO5L-ybjbN9ZQiMq5N0UduIaL9pIDHYJw62scX0R5xoCZqXKkjqUKYFavHCRqcLhgww1nBYl414GOfqZeGz1yCfd-kfl3XOJxiAfNog-gt5ZMMcvRQwhjSMoX5/s1600/screen3.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0B9MFJCQuhlSHk7ziTNTO5L-ybjbN9ZQiMq5N0UduIaL9pIDHYJw62scX0R5xoCZqXKkjqUKYFavHCRqcLhgww1nBYl414GOfqZeGz1yCfd-kfl3XOJxiAfNog-gt5ZMMcvRQwhjSMoX5/s320/screen3.jpg" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Click to enlarge</td></tr></tbody></table><br /><br /><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEixdXLTisQC8eDJSjW2sicQz06WcV2nsSYMA4ecn2_6zDQb5k0q5qD60rEXlxVM1IN-mrUS73TjB1dN1q6BGL1stWms-99PJqTw0pMMauASbx2YEb6D-aho7yWPtuzx97lC-u8TQii0XGTc/s1600/screen4.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="213" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEixdXLTisQC8eDJSjW2sicQz06WcV2nsSYMA4ecn2_6zDQb5k0q5qD60rEXlxVM1IN-mrUS73TjB1dN1q6BGL1stWms-99PJqTw0pMMauASbx2YEb6D-aho7yWPtuzx97lC-u8TQii0XGTc/s320/screen4.jpg" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Click to enlarge</td></tr></tbody></table><br /><br /><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgF0KBIoGM5O3qs9gWxR5sFvdW4ScqaaMSxKT4MhwvC2WV15pBswtWoC4C9dWHLsIq1N8v82loQM_4t6bg4B_dMR47MsYzuOKwS54JwxXCY9SeSLqLjMuZMzGKj_OSatVP2zGLL7aaAY1cW/s1600/screen5.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="198" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgF0KBIoGM5O3qs9gWxR5sFvdW4ScqaaMSxKT4MhwvC2WV15pBswtWoC4C9dWHLsIq1N8v82loQM_4t6bg4B_dMR47MsYzuOKwS54JwxXCY9SeSLqLjMuZMzGKj_OSatVP2zGLL7aaAY1cW/s320/screen5.jpg" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Click to enlarge</td></tr></tbody></table><br /><br /><br />And there's more where these came from at the link above.<br /><br />Insane, in my view, to subject busy, stressed out clinicians to a pastel nightmare like this. <br /><br />(And that's assuming the application doesn't lose or corrupt data.)<br /><br />This is not to single out this particular seller.  Other EHR sellers' products are similarly visually and operationally complex.<br /><br />But, if you, the reader, like these and think, the more that can be packed in the merrier, bring it on, that's fine with me.  It's your life and limb.<br /><br />Actually, not - because my life and limb are at risk, too.<br /><br />See the entire presentation for more.<br /><br />-- SS<br /><br /><br />

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EHR Pastel Madness: Cognitive Overload in Critical Care

It's hard to find public postings that show the crazy and dangerous complexity of EHR interfaces, but I found a presentation at http://www.uiowa.edu/~medtest2/picis/vo_picis.pdf (PDF slide presentatio…

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How Manipulated Clinical Evidence Could Distort Guidelines - the Case of Statins for Primary Prevention

The new American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines on the primary prevention of cardiovascular disease, which we discussed <a href="http://hcrenewal.blogspot.com/2013/11/confused-thinking-about-new-cholesterol.html">here</a>, continue to generate controversy.  <br /><br />Articles in the media and online-first in medical journals underscored some of the issues we discussed before.  Jeanne Lenzer, in a news article in the British Medical Journal, found that the chair of the guideline panel had important past conflicts of interest that were not previously disclosed.(1)  The chair denied their significance (look <a href="http://healthland.time.com/2013/11/22/conflicts-of-interest-cholesterol-panel-head-defends-members-ties-to-industry/">here</a>).   Guideline panel members continued to justify their efforts, but in my humble opinion, raised no new evidence or logic to support it (look <a href="http://www.medscape.com/viewarticle/814711">here</a>  and <a href="http://www.medscape.com/viewarticle/814960">here</a>)<br /><br /><b>Bigger Questions about the Validity of the Clinical Evidence </b><br /><br />However, several new articles suggested the need for a deeper look at one particular aspect of this case, the validity of the evidence from clinical research about the benefits and harms of statins for primary prevention.<br /><br />JAMA published a summary of the Cochrane review that provided a basis for the guideline developers' confidence in the worth of statin therapy in primary prevention.(2)<br /><br /><blockquote class="tr_bq"><span class="Paragraph 45021753" id="scm6MainContent_ucArticleContent_rptSections_lblSection_8"> results suggest that the benefits of statin therapy outweigh serious life-threatening hazards.</span></blockquote><br /><span class="Paragraph 45021753" id="scm6MainContent_ucArticleContent_rptSections_lblSection_8">However, almost as an aside, it noted,</span><br /><br /><blockquote class="tr_bq"><span class="Paragraph 45021760" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12">Some trials included participants with CVD, but rather than exclude these trials, we <b><i>included trials that contained 10% or fewer participants with documented CVD.</i></b></span></blockquote><br /><span class="Paragraph 45021760" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12">Primary prevention in this case is defined as prevention for patients without existing cardiovascular disease.  There is evidence that statins may well have benefits that outweigh harms when given to patients with known cardiovascular disease, particularly documented coronary artery disease (CAD).  Mixing such patients in any numbers into "primary prevention trials" would likely exaggerate the benefits of statins.  Yet such not quite primary prevention studies were included in a systematic review of primary prevention.  </span><br /><span class="Paragraph 45021760" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12"><br /></span><span class="Paragraph 45021760" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12">In addition, a commentary by one of the guideline developers defending the group's work also underscored the fact that many of the supposedly primary prevention trials they used as evidence were not pure primary prevention trials.(3)</span><br /><span class="Paragraph 45021760" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12"><br /></span><br /><blockquote class="tr_bq"><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">Notably, the 2013 cholesterol guideline cut points were derived from the placebo rates for myocardial infarction, stroke, and cardiovascular disease death observed in the <b><i>3 exclusively primary prevention statin trials</i></b>, Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, and the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).[4-6]</span></blockquote><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">The wording again suggests that all the other trials used as evidence about primary prevention were NOT "exclusively primary prevention studies," and hence, as I noted above, may have been biased so that they would likely exaggerate the apparent benefits of statins in primary prevention.</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">This suggested to me that the systematic review that provided a basis for the guidelines' aggressive recommendations about statins for primary prevention, and the trials on which it was based needed further skeptical, critical reviews.</span><br /><br /><b><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">The Cochrane Review: Was Evidence about Statin Benefits vs Harms Manipulated?</span></b><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">We have frequently discussed the <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation of clinical research</a>.  By that we have meant design, implementation, analysis or dissemination of research in ways likely to further vested interests.  In particular, when drug, biotechnology and device companies sponsor and control clinical research on their own products, they may set up the research in ways likely to make their products look better than they actually are.  </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">We looked through the most recent Cochrane review of statins for primary prevention(7) with a skeptical eye out for suggestions that the trials reviewed could have been so manipulated.  We found quite a bit.</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">First, we found that not all trials reported on the "hard" outcomes that one needs to consider when evaluating benefit vs harm of statins in primary prevention.</span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><br /><blockquote class="tr_bq"><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">Data on all-cause mortality were provided in 11 trials.[of 19, and hence missing in 8].</span></blockquote><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">And,</span><br /><br /><blockquote class="tr_bq"><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"> Twelve trials provided data on adverse events.[and hence 7 did not.]</span></blockquote><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"> Also, data on specific adverse events was often not reported: myalgia and rhabdomyolysis were reported in only 9/19 trials; new onset diabetes mellitus in only 2/18; hemmorhagic stroke in only 2/19; abnormal liver tests in only 10/19; kidney dysfunction in only 4/19; arthritis in only 2/19, and by implication, cognitive dysfunction in 0/19.  </span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span>  <span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">Failure to look for all the possible bad outcomes of treatment could obviously bias the study in the direction of minimizing the harms of the treatment.</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">A substantial number of trials either failed to report on crucial aspects of their methods, or admitted to flaws that could have induced important biases.: 3/19 did not described randomization methods; 4/19 did not use double-blinding; 6/19 did not use intention to treat analysis; 7/19 did not report their drop-out rates.</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">So it is very surprising to me that the authors concluded,</span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><br /><blockquote class="tr_bq"><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">In general there was low risk of bias ... though all trials were either fully or partially funded by pharmaceutical companies.</span></blockquote><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">In my humble opinion, the Cochrane review showed many trials that had flaws could have biased their outcomes, and hence the outcomes of the overall review.  Some of the flaws clearly could have lead to biases that would have made statins look more efficacious, or less dangerous than they might actually be.</span>  <span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">I do not understand the conclusion that the risk of bias was slow, and the lack of discussion about the direction the bias could have taken. </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"> <b>Review of the "3 Exclusively Primary Prevention Statin Trials"</b></span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">Given the Cochrane review's apparent lack of skepticism about methodologic problems in the industry funded statin prevention trials, I endeavored to take a closer look at the three trials that Dr Robinson held out as the real primary prevention trials.  Instances of manipulation, as we defined it above, for each trial are described below </span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>AFCAPS/ TexCAPS</u>(4)</span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Narrow Patient Population</u> - This study excluded many patient for whom the statins were not contraindicated or warned against: uncontrolled hypertension; type 1 or type 2 diabetes mellitus on insulin or with a HgBA1C at least 10%; and body weight more than 50% "desirable limit for height."  (Based on the official contraindications and warnings for commonly used statins, e.g., see contraindications for Lipitor <a href="http://labeling.pfizer.com/ShowLabeling.aspx?id=587">here</a>, active liver disease, pregnancy for likely to become pregnant, nursing mothers, hypersensitivity to the medicine; and warnings: use of cyclosprine or strong CYP3A4 inhibitors, uncontrolled hypothyroidism, renal impairment.)  Thus the results may not generalize to many patients who would otherwise be considered statin candidates.  By excluding such patients, the results may bias the study towards minimizing the probabilities of harms that might occur were statins used on a wide population for primary prevention.</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Unknown Randomization and Allocation Concealment Procedures</u> - According to the Cochrane Review, the study report did not explain how randomization or allocation concealment were accomplished.   </span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Early Termination/ Multiple Comparisons</u> - The study was terminated early based on an early look at the number of outcome events.  Two such early or interim analyses were planned.  Taking multiple looks at the data over time raises a multiple comparisons problem, and may lead to exaggerating the benefits of the treatment.(8). Furthermore, stopping early decreases the sample size and hence the power to find adverse effects of treatment.</span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Implausible Dropout Rate, Missing Data</u> - According to the Cochrane Review, the study reported no dropouts.  This seems somewhat improbable, suggesting skepticism about the accuracy and completeness of the data collection.  On the other hand, a study chronology suggests that of 6605 patients who started the study, 6540 had data on complete endpoint status, suggesting missing data.  Since dropouts and missing data may be due to different reasons in different arms of the study, they threaten the validity of data about benefits and harms.  </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Adverse Effects not Reported</u> - The study provided no data about development of diabetes, hemmorhagic stroke, kidney dysfunction, arthritis, or cognitive dysfunction, suggesting incomplete data about harms, and hence bias towards minimizing harms.    </span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>MEGA</u> (5)</span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"></span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Narrow Patient Population</u> -  [The patient population was not described in the main report, but only in an earlier methods article.](9)  The study excluded patients with congenital or rheumatic heart disease; chronic atrial fibrillation, current diagnosis of malignancy; poorly controlled hypertension or diabetes mellitus; current use of oral or parenteral corticosteroids; and other conditions at the discretion of the physician.  These exclusions seem unrelated to the contraindications or warnings on the stain label.  Again, such a narrow patient population reduces the generalizability of the study results, and may bias the study to minimizing the harms of statins.</span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"></span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Only Single Blind</u> - This was an open-label study, so patients and physicians knew who got statins and who got placebo.  Such knowledge could have biased patient management, including how diligently particular diagnoses and outcomes were pursued, and biased data collected from patients or physicians.</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Adverse Effects Not Reported</u> - The study provided no data about diabetes, hemmorhagic stroke, kidney dysfunction, arthritis, or cognitive dysfunction, again suggesting bias towards minimizing harms.  </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>JUPITER</u>(6)</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Narrow, Unusual Patient Population</u> - The study was limited to patients without hyperlipidemia but with an increased C-reactive protein.  Thus it is not clear that its results would generalize to a more typically defined primary prevention population.  The study excluded patients receiving post-menopausal hormone-replacement; with diabetes; uncontrolled hyertension; cancer other than non-melanoma skin cancer within 5 years; recent history of drug or alcohol abuse; "another medical condition that might compromise safety or the successful completion of the study;" also patients with "inflammatory conditions such as severe arthritis, lupus, or inflammatory bowel disease...;" and also "patients taking immunosuppressant agents such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids."  Again, this narrow patient population would reduce generalizability and bias towards minimizing harms.</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Early Termination/ Multiple Comparisons </u>- This study was terminated early after an early look at the data.  Allowing for multiple looks at the data may exaggerate efficacy.  </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Implausible Dropout Rate</u> - According to the Cochrane Review, the study had no dropouts.  This value seems implausible, again suggesting data collection problems.   </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><u>Adverse Effects Not Reported</u> - The study provided no data about <strike>hemmorhagic stroke</strike>, arthritis, or cognitive dysfunction, again suggesting bias towards minimizing harms.  [Revised December 9, 2013 - see comment below by Marilyn Mann.] </span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><b><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">Summary</span></b><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">Aspects of the continuing controversy over the new ACC/ AHA guidelines for statins in the primary prevention of cardiovascular disease hinted that the clinical trials which provided the evidentiary basis for the guidelines, and for the use of statins in primary prevention in general, was more flawed than is widely appreciated.  The latest Cochrane Collaboration review of this data acknowledged multiple, important flaws affecting most of the studies.  Our more detailed review of the three studies held out as the purest found additional flaws.  Many of these flaws seemed likely to bias the studies towards exaggerating the efficacy and/or minimizing the harms of statins in primary prevention.  Since all these trials were funded, and presumably influenced by pharmaceutical companies that make statins, these flaws seem to be examples of <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation of the clinical evidence</a>.  Rather than being the result of simple mistakes, or inevitable trade-offs, they seem to be study features intended the support the vested interests of the study sponsors.</span><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5"><br /></span><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">It is not clear why the Cochrane review did not temper its conclusions based on the flaws in the studies, and particularly by the possibility that these flaws represented study manipulation.  </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">The multiple flaws, possibly due to study manipulation, in the clinical evidence about statins in primary prevention suggest that we should be extremely skeptical about whether the benefits of such treatment outweighs its harms, and hence about whether the recommendations in the latest guidelines to give statins to all patients predicted (but perhaps not accurately) to be at even slightly elevated risk are warranted.</span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">The flaws in multiple large studies of a very common clinical problem, and their effects on systematic reviews and clinical practice guidelines suggest that suppression and manipulation of research are rife in medicine and health care, presumably fueled by the pervasive web of <a href="http://hcrenewal.blogspot.com/search/label/conflicts%20of%20interest">conflicts of interes</a>t that spans health care.  We need extreme skepticism about the integrity of clinical research, especially research sponsored by those whose products and services are being studied, and who thus have vested interests in the research turning out to make their products and services look good.   </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">The good news is that we may not have to look too far to find ways to improve the trustworthiness of guidelines and the soundness of medical decision making.  Implementation of the Institute of Medicine's recommendations on reducing conflicts of interest (look <a href="http://www.iom.edu/Activities/Workforce/ConflictOfInterest.aspx">here</a>), and developing trustworthy guidelines (look <a href="http://www.iom.edu/Activities/Quality/ClinicPracGuide.aspx">here</a>) might lead to the development of sound guidelines in the future.  </span><br /><br /><span class="Paragraph 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_5">Furthermore, while endless discoveries of <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulated</a> and <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppressed research</a> may have lead some <a href="http://hcrenewal.blogspot.com/search/label/evidence-based%20medicine">evidence-based medicine </a>advocates to despair, our latest exercise suggests that the principles of evidence-based medicine, unflinchingly applied, could really do good.  Review of the three statin studies above based on standard principles of critical review readily spotted the multiple signs of manipulation.  The problem with the Cochrane review was not that it missed these signs.  Rather, the reviewers for some reason noted most of them, but then did not react.  If systematic reviews were done with sufficient skepticism about the possibility of manipulation of clinical research, and were willing to call out when the emperor seemed short on fabric, then a lot of mischief could be avoided.   </span><br /><br /><br /><b>References</b><br /><br />1.  Lenzer J. Majority of panelists on controversial new cholesterol guideline have current or recent ties to drug manufacturers.  Brit Med J 2013.  Link<a href="http://www.bmj.com/content/347/bmj.f6989"> here</a>.  <br /><br />2.  Taylor FC, Huffman M, Shah E. Statin therapy for primary prevention of cardiovascular disease.  JAMA 2013.  Link <a href="http://jama.jamanetwork.com/article.aspx?articleid=1785551">here</a>.   <br /><br />3.  Robinson JG.  Accumulating evidence for statins in primary prevention.  JAMA 2013;  Link <a href="http://jama.jamanetwork.com/article.aspx?articleid=1785550">here</a>. <br /><br />4.    <span class="References 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12">Downs  JR, Clearfield  M, Weis  S,  et al; for the AFCAPS/TexCAPS Research Group.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. <i>JAMA</i>. 1998;279(20):1615-1622. Link <a href="http://dx.doi.org./10.1001/jama.279.20.1615">here</a>. </span><br /><span class="References 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12"></span><span class="References 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12">5.  </span><span class="References 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12">Nakamura  H, Arakawa  K, Itakura  H,  et al; MEGA Study Group.  Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA study): a prospective randomised controlled trial. <i>Lancet</i>. 2006;368(9542):1155-1163. Link <a href="http://dx.doi.org./10.1016/S0140-6736(06)69472-5">here</a>.</span><br /><br /><span class="References 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_12">6.  Ridker  PM, Danielson  E, Fonseca  FA,  et al; JUPITER Study Group.  Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. <i>N Engl J Med</i>. 2008;359(21):2195-2207. Link <a href="http://dx.doi.org./10.1056/NEJMoa0807646">here</a>.  </span><br /><br />7.  Taylor F,  Huffman MD, Macedo AF et al.  Statins for the prevention of cardiovascular disease. Cochrane Library 2013.  Link <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004816.pub5/abstract">here</a>.<br /><br />8. Mueller PS, Montori VM, Bassler D et al.  Ethical issues in stopping randomized trials early because of apparent benefit.  Ann Intern Med 2007; 146: 878-881.  Link <a href="http://annals.org/article.aspx?articleid=735073">here</a>.   <br /><br />9.  Management of Elevated Cholesterol in the Primary Prevention Group of the Adult Japanese (MEGA) Study Group.  Design and baseline characteristics of a study of primary prevention of coronary events with pravastatin among Japanese with mildly elevated cholesterol levels.  Circ J  2004; 68: 860-867.  Link <a href="http://www.ncbi.nlm.nih.gov/pubmed/15329509">here</a>.

How Manipulated Clinical Evidence Could Distort Guidelines - the Case of Statins for Primary Prevention

The new American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines on the primary prevention of cardiovascular disease, which we discussed here, continue to generate controversy…

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There They Go Again, Again... - Johnson and Johnson Loses Two Civil Cases, Makes $2.5 Billion Settlement Based on Claims it Withheld Safety Data on its Products

There has been some talk by US government officials that any day now they will actually get tough on corporate executives whose organizations are involved in multiply unethical actions (perhaps using the legally valid, but massively neglected responsible corporate officer doctrine, look <a href="http://hcrenewal.blogspot.com/2010/06/attempt-to-hold-health-care-leaders.html">here</a>).  However, the <a href="http://hcrenewal.blogspot.com/search/label/legal%20settlements">march of legal settlements</a> by such corporations continue without any hints of negative consequences for the people who might have actually been involved in unethical activity.  <br /><br />So, we note another week, another multi-billion dollar settlement and another loss of a civil lawsuit by huge drug, device and biotechnology company <a href="http://hcrenewal.blogspot.com/search/label/Johnson%20and%20Johnson">Johnson and Johnson</a><br /><br /><b>The Articular Surface Replacement Metal-on-Metal Hip Prosthesis Settlement</b><br /><br />After various rumors, the report of the settlement appeared in a New York Times <a href="http://www.nytimes.com/2013/11/20/business/johnson-johnson-to-offer-2-5-billion-hip-device-settlement.html">article</a> on November 19, 2013.  The basics were,<br /><br /><blockquote class="tr_bq">Johnson & Johnson and lawyers for patients injured by a flawed hip implant announced a multibillion-dollar deal on Tuesday to settle thousands of lawsuits, but it was not clear whether the deal would satisfy enough claimants.<br /><br /><div itemprop="articleBody">Under the agreement, <i>the medical products giant would pay nearly $2.5 billion in compensation to an estimated 8,000 patients who have been forced to have the all-metal artificial hip removed and replaced with another device. </i></div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">Separately, the company has agreed to pay all medical costs related to such procedures, expenses that could raise the deal’s cost to Johnson & Johnson to $3 billion, people familiar with the proposal said. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">Under the plan, the typical patient payment for pain and suffering caused by the device would be about $250,000 before legal fees. Based on standard agreements, plaintiffs’ lawyers would receive about one-third of the overall payout, or more than $800 million, with those who negotiated the plan emerging as big winners. </div><br />The proposed settlement, which was submitted on Tuesday to a federal judge in Toledo, Ohio, must receive the support of 94 percent of eligible claimants to go forward.</blockquote><br />An <a href="http://www.nytimes.com/2013/11/13/business/johnson-and-johnson-said-to-agree-to-4-billion-settlement-over-hip-implants.html">earlier NY Times article </a>on a rumored version of the settlement emphasized that relevant litigation had featured strong allegations that Johnson  and Johnson's DePuy subsidiary hid what it knew about the faults of the device,<br /><br /><br /><blockquote class="tr_bq"><div itemprop="articleBody">The A.S.R. hip was sold by DePuy until mid-2010, when the company recalled it amid sharply rising early failure rates. The device, which had a metal ball and a metal cup, sheds metallic debris as it wears, generating particles that have damaged tissue in some patients or caused crippling injuries. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">DePuy officials have long insisted that they acted appropriately in recalling the device when they did. However,<i> internal company documents disclosed during the trial of a patient lawsuit this year showed that DePuy officials were long aware that the hip had a flawed design and was failing prematurely at a high rate. </i></div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">Many artificial hips last 15 years or more before they wear out and need to be replaced. But by 2008, data from orthopedic databases outside the United States also showed that the A.S.R. was failing at high rates in patients after just a few years. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">Internal DePuy projections estimate that it will fail in 40 percent of those patients in five years, a rate eight times higher than for many other hip devices. </div></blockquote><div itemprop="articleBody"><br /></div><div itemprop="articleBody">A <a href="http://www.nytimes.com/2013/11/26/business/frustration-from-a-deal-on-flawed-hip-implants.html">later NY Times article</a> about plaintiffs' sometimes negative reactions to the settlement added,</div><div itemprop="articleBody"><br /></div><blockquote class="tr_bq"><div itemprop="articleBody"> The DePuy Orthopaedics division of Johnson & Johnson estimated in an internal document in 2011 that the device would fail within five years in 40 percent of patients. Traditional artificial hips, which are made of metal and plastic, typically last 15 years or more before replacement. </div><div itemprop="articleBody"><br /></div></blockquote><div itemprop="articleBody"><blockquote> <i>DePuy officials have insisted that they acted properly in handling the device, including waiting until 2010 to recall it. However, internal company documents show that company officials were warned years before by their own consultants that the device was so problematic they would not use it in their patients. </i></blockquote><br />In January, 2013, the NY Times had <a href="http://www.nytimes.com/2013/01/26/business/johnson-johnson-hid-flaw-in-artificial-hip-documents-show.html">reported</a> in more detail about how DePuy executives concealed evidence about safety issues with the hips,<br /><br /><blockquote class="tr_bq">. <i>Johnson and Johnson executives knew years before they recalled a troubled artificial hip in 2010 that it had a critical design flaw, but the company concealed that information from physicians and patients</i>, according to internal documents disclosed on Friday during a trial related to the device’s failure.<br /><br /><div itemprop="articleBody"><i>The company had received complaints from doctors about the device, the Articular Surface Replacement, or A.S.R., even as it started marketing a version of it in the United States in 2005. </i>The A.S.R.’s flaw caused it to shed large quantities of metallic debris after implantation, and <i>the model failed an internal test in 2007</i> in which engineers compared its performance to that of another of the company’s hip implants, the documents show. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody"><i>Still, executives in Johnson & Johnson’s DePuy Orthopaedics unit kept selling the A.S.R. even as it was being abandoned by surgeons who worked as consultants to the company. DePuy executives discussed ways of fixing the defect, the records suggest, but they apparently never did so. </i></div></blockquote></div><blockquote><div itemprop="articleBody">Plaintiffs’ lawyers introduced the documents on Friday in Los Angeles Superior Court during opening arguments in the first A.S.R.-related lawsuit to go to trial.</div></blockquote><div itemprop="articleBody"></div><div itemprop="articleBody">In particular, </div><div itemprop="articleBody"></div><div itemprop="articleBody"><blockquote class="tr_bq"><div itemprop="articleBody">In 2007, DePuy engineers tested the A.S.R.’s rate of wear to see if it matched the wear rate of another all-metal hip implant made by the company. It did not. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody"><i>'The current results for A.S.R. do not meet the set acceptance criteria for this test,' that report stated.</i></div><div itemprop="articleBody"><br /></div><div itemprop="articleBody"><i>The same year, company officials began discussing ways to fix the problem, like redesigning the cup</i> to eliminate the groove. But <i>at the same time, it was actively marketing the A.S.R. to surgeons in the United States</i>, who were implanting it into tens of thousands of patients. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">'<i>We will ultimately need a cup redesign, but the short-term action is <b>manage perceptions</b>,'</i> one top DePuy sales official told a colleague in a 2008 e-mail. <i>A DePuy executive, <b>Andrew Ekdahl, who is now the unit’s president</b>, was also told by a company consultant that the A.S.R. was flawed,</i> according to another document. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">In mid-2008, DePuy apparently abandoned the redesign project, an internal document indicates. A company spokeswoman, Mindy Tinsley, declined to comment on the document. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">In the fall of 2009, the Food and Drug Administration rejected DePuy’s application to sell the resurfacing version of the A.S.R. in the United States, saying it was concerned about, among other things, “high concentration of metal ions” in the blood of patients who received it. </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">DePuy executives soon started making financial estimates of when the company should stop selling the A.S.R., based on the time it would take to convert surgeons to another company implant, a document shows.</div></blockquote><div itemprop="articleBody"><br /></div><div itemprop="articleBody">So the evidence introduced in litigation suggested that top DePuy executives knew the design was faulty, but chose to not disclose the evidence of this, and not to withdraw the product, but rather to "manage perceptions."  </div></div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">As is typical of most settlements made by big health care corporations in the last 10 years, no one at DePuy or its Johnson and Johnson parent who might have authorized, directed, or implemented the continued sales of the device despite warnings that it might be unsafe would have to suffer any negative consequences.  In particular, apparently Mr Ekdahl will not suffer any such consequences (and was not obviously named in the few news reports of the settlement.)   Mr Ekdahl, now Worldwide President, DePuy Synthes Joint Reconstruction, was quoted in the official Johnson and Johnson <a href="http://www.investor.jnj.com/releasedetail.cfm?ReleaseID=808497">news release</a> about the settlement.<br /><b><br /></b></div><div itemprop="articleBody"></div><div itemprop="articleBody"><b>The Topamax Verdicts</b></div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">This case, which was much smaller in terms of the monetary amounts involved, got much less coverage, but Bloomberg did <a href="http://www.bloomberg.com/news/2013-11-18/j-j-s-janssen-loses-11-million-jury-verdict-over-topamax.html">report</a> on November 18, 2013,</div><div itemprop="articleBody"><br /></div><blockquote class="tr_bq"><div itemprop="articleBody">Johnson & Johnson's  Janssen Pharmeceuticals unit was <i>ordered by a Philadelphia jury to pay $11 million</i> in a case claiming its anti-seizure drug Topamax caused birth defects,<i> the second such loss in less than a month.</i></div></blockquote><div itemprop="articleBody"><br /></div><div itemprop="articleBody">Again, the case involved claims that the company withheld information about the safety of its product,</div><div itemprop="articleBody"><br /></div><blockquote class="tr_bq"><i>Janssen failed to adequately warn doctors </i>for Haley Powell, a stay-at-home mother, of the risks of Topamax before she gave birth to a son with a cleft lip,<i> jurors in state court in Philadelphia found today.</i><br /><br />'Janssen has long known that this drug causes debilitating birth defects and yet <i>intentionally kept this information from physicians and patients,</i>' Shelley Hutson, an attorney for Powell, said after the verdict was read.</blockquote><br />Furthermore,<br /><br /><blockquote class="tr_bq"><i> Janssen knew as early as 1997 that animal studies showed an increased risk for birth defects</i>, especially oral clefts, Hutson said during closing arguments on Nov. 15.<br /><br /><br />Hutson accused Janssen of <i>operating in a culture of secrecy and of intentionally concealing safety reports in 2003 and 2005.</i>She rejected arguments by the company that it presented the information on poster boards, in abstracts and at medical conferences. Those actions “do not keep patients safe,” Hutson said.<br /><br />'As early as 1997 in admission after admission, this company knew and they didn’t tell the doctors,' Hutson said.</blockquote><br />A <a href="http://www.law360.com/articles/489739">report</a> in Law360 emphasized,<br /><br /><blockquote class="tr_bq"> Plaintiffs in the Pennsylvania suits <i>alleged the company didn't fully, truthfully or accurately disclose Topamax data to the FDA, to them and to their doctors. As a result, Janssen intentionally and fraudulently misled the medical community, the public and herself </i>about the risks to a fetus associated with the use of Topamax during pregnancy, plaintiffs claimed.</blockquote><br /><b> Summary</b><br /><br />There they go again....  So Johnson and Johnson has announced two multi-billion dollar settlements in one month (November, 2013, look <a href="http://hcrenewal.blogspot.com/2013/11/another-and-huge-22-billion-settlement.html">here</a> for the first).  It also announced a smaller settlement involving the marketing of Topamax, which is now in addition to a 2010 guilty plea for misbranding Topamax in 2010 (look <a href="http://hcrenewal.blogspot.com/2013/11/another-and-huge-22-billion-settlement.html">here)</a>.  Note that all the November, 2013 legal actions involved allegations, often backed by seemingly convincing evidence produced in litigation (as noted above), of deceptive, unethical practices.  Both cases above included allegations that the company sold products without fully disclosing those products' harms to patients.  Furthermore, all the month's legal actions are now added to a long list of Johnson and Johnson's legal woes, often involving allegations and evidence of other unethical actions, sometimes involving guilty pleas to charges of such actions (see compilation of the record through July, 2013 <a href="http://hcrenewal.blogspot.com/2013/07/johnson-and-johnson-settles-suit.html">here</a>.)  (By the way, Synthes, which is now another Johnson and Johnson subsidiary, and is not run by the same individual on whose watch the ASR case occurred, has had its own legal and ethical woes, look <a href="http://hcrenewal.blogspot.com/search/label/Synthes">here</a>.)  <br /><br />Yet despite this lengthy and sorry record, no individual manager or executive at Johnson and Johnson, including its many and confusing subsidiaries, seems to have suffered any negative consequences for authorizing, directing, or implementing any unethical activities, whether they risked harming patients, or whether they resulted in a guilty plea by a corporate entity.  Instead, as we have discussed most recently <a href="http://hcrenewal.blogspot.com/2013/11/another-and-huge-22-billion-settlement.html">here</a>, the top executives of the company have grown very rich.  <br /><br />So since the US government seems to continue to recycle its policy of allowing corporate managers and executives impunity regardless of how repetitively harmful their actions might be to patients' and the public's health, I will recycle my comments from earlier in November, 2013,....<br /><br />The latest settlement in the parade is another marker of the sort of conduct that big health care organizations have exhibited to increase revenue, and to use that revenue as a rationale for making their top insiders very rich.  The particular conduct alleged here could have put patients at risk, partly by deceiving health care professionals.  Yet in their wisdom, top US law enforcement saw fit not to try to hold any individuals accountable for this conduct, and allowed the company to deny any misconduct other than a single misdemeanor by a subsidiary.  This occurred despite the company's history of multiple legal settlements and findings of guilt in various courtrooms.<br /><br />Yet none of these actions has resulted in any negative consequences for any individual within the company.  No one who authorized, directed, or implemented bad behavior will pay any penalty, even were the bad behavior to have lead to significant personal enrichment.<br /><br />As we have said ad infinitum, and <a href="http://hcrenewal.blogspot.com/2012/09/how-many-legal-settlements-does-it-take.html">on the occasion of a previous Johnson and Johnson settlement</a>, many of largest and once proud health care organizations now have recent records of repeated, egregious ethical lapses. Not only have their leaders have nearly all avoided penalties, but they have become extremely rich while their companies have so misbehaved. <br /><br />These leaders seem to have become like nobility, able to extract money from lesser folk, while remaining entirely unaccountable for bad results of their reigns. We can see from this case that health care organizations' leadership's nobility overlaps with the supposed "royalty" of the leaders of big financial firms, none of whom have gone to jail after the global financial collapse, great recession, and ongoing international financial disaster (look <a href="http://hcrenewal.blogspot.com/2012/08/duchess-of-wellpoint-abdicates-likely.html">here</a>). The current fashion of punishing behavior within health care organization with fines and agreements to behave better in the future appears to be more law enforcement theatre than serious deterrent.  As Massachusetts Governor Deval Patrick exhorted his fellow Democrats, I exhort state, federal (and international, for that  matter) law enforcement to "<a href="http://www.washingtonpost.com/blogs/election-2012/wp/2012/09/04/patrick-it-is-time-for-democrats-to-grow-a-backbone/">grow a backbone</a>" and go after the people who were responsible for and most profited from the ongoing ethical debacle in health care.<br /><br />As we have said before, true health care reform would make leaders of health care organization accountable for their organizations' bad behavior.<br /><br />Roy M. Poses MD on Health Care Renewal  <br /><br />

There They Go Again, Again... - Johnson and Johnson Loses Two Civil Cases, Makes $2.5 Billion Settlement Based on Claims it Withheld Safety Data on its Products

There has been some talk by US government officials that any day now they will actually get tough on corporate executives whose organizations are involved in multiply unethical actions (perhaps using …

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Confused Thinking about New Cholesterol Guidelines - Were Conflicts of Interest to Blame?

For years, clinical practice guidelines promulgated by prominent health care organizations have been hailed with accolades as received wisdom.  However, there is increasing reason to be skeptical of such guidelines.  Many guidelines are not based on rigorous application of the principles of <a href="http://hcrenewal.blogspot.com/search/label/evidence-based%20medicine">evidence-based medicine,</a> and often seem to arise from the personal opinions of their authors.  This is particularly troublesome when those authors  have conflicts of interest, and when the organizations that sponsor guideline development have institutional conflicts of interest.  Back in 2011, an Institute of Medicine panel advocated standards for guideline development, including strict limits on conflicted panel members, to make their results more trustworthy.  However, as we noted <a href="http://hcrenewal.blogspot.com/2012/11/what-if-institute-of-medicine-wrote.html">here</a>, those standards have been largely ignored.    <br /><br />Therefore, it is good news that the just released, long awaited guidelines on the treatment of blood cholesterol from the American College of Cardiology (ACC) and American Heart Association (AHA)(1)  they provoked controversy rather than adulation.  However, connecting some dots reveals that the guideline development process and the defenses of the guidelines by its developers were even more confused than they first seemed.  That confusion may be explained by conflicts of interest affecting guideline development of the sort that the IOM report wanted eliminated.  .<br /><br /><br /><b>The New Cholesterol Guidelines - Background</b><br /><br />A striking feature of the guidelines was a new approach to drug treatment for primary prevention, that is, for patients who do not already have heart disease or other atherosclerosis.   Such drug based primary prevention has been controversial, although drug treatment for people with high cholesterol who also have documented coronary heart disease, secondary prevention, is well-established.<br /><br />The new cholesterol treatment guideline suggested drug treatment, essentially limited to statin medications, for patients believed to be at elevated risk of developing coronary artery disease or other forms of atherosclerotic disease, even in the absence of elevated cholesterol levels.   <br /><br /><blockquote class="tr_bq">Adults 40 to 75 years of age with LDL–C [so called "bad cholesterol"] ]70 to 189 mg/dL, without clinical ASCVD* [atherosclerotic cardiovascular disease] or diabetes and an estimated 10-year ASCVD risk ≥7.5% should be treated with moderate- to high-intensity statin therapy.</blockquote><br />Also,<br /><br /><blockquote class="tr_bq">It is reasonable to offer treatment with a moderate intensity statin to adults 40 to 75 years of age, with LDL–C 70 to 189 mg/dL, without clinical ASCVD* or diabetes and an estimated 10-year ASCVD risk of 5% to [less than] ... 7.5% </blockquote><br />Previously, guidelines and other recommendations for the treatment of cholesterol for primary prevention, that is, for patients without known atherosclerotic cardiovascular disease, suggested treatments according to the level of cholesterol or its components.   <br /><br />Less controversially, the guidelines recommended treatment for patients with existing ASCVD, very high LDL-C, and diabetes.<br /><br />The new guidelines raise some  questions:<br />- Given the past controversy, how good is the evidence supporting cholesterol lowering drug treatment in primary prevention?<br />- What is the evidence supporting deciding on drug treatment for primary prevention on predicted risk of atherosclerotic cardiovascular disease?<br />- Can physicians make good enough risk predictions to use this approach?<br /><br /><b>Evidence Supporting Drug Treatment of Cholesterol in Primary Prevention - Do Benefits Outweigh Harms?</b><br /><br />The reason that cholesterol lowering drug use for primary prevention has been controversial is the lack of clear evidence that such drug use leads to benefits to patients that outweigh its harms.  A central principle of evidence based medicine is that only treatments whose benefits clearly outweigh their harms should be prescribed.  .<br /><br />A recent commentary by Abramson et al in the British Medical Journal in October, 2013 outlines the issues.(2)  There is no good evidence that statins used in primary prevention increase overall survival, or decrease overall incidence of adverse events, defined as death, hospital admission, prolongation of admission, cancer or permanent disability.<br /><br />Individual trials and meta-analyses do show that statins lead to a small reduction in the rate of cardiovascular events.  For example, the authors' re-analysis of data from a patient level meta-analysis showed that of 140 low-risk primary prevention patients treated for five years, one patient would avoid a major coronary event or stroke.<br /><br />However, it is not clear that this small likelihood of benefit offsets the likelihood of adverse events due to treatment.  The data about the harms of statins in primary prevention is not very clear, partially because the relevant randomized controlled trials featured "reporting of adverse events ... [that was] generally poor, 'with failure to provide details of severity and type of adverse events or to report on health-related quality of life."<br /><br />In summary, Abramson et al wrote,<br /><br /><blockquote class="tr_bq">statin therapy prevents one serious cardiovascular event per 140 low risk people (five year risk ... [less than] 10%) treated for five years.  Statin therapy in low risk people does not reduce all cause mortality or serious illness and has about an 18% risk of causing side effects that range from minor and reversible to serious and irreversible.  Broadening the recommendations in cholesterol lowering guidelines to include statin therapy for low risk individuals will unnecessarily increase the incidence of adverse effects without providing overall health benefit.</blockquote><br />However, the new guideline focused on the ability of statins to prevent ASCVD,  <br /><br /><blockquote class="tr_bq">The RCTs identified in the systematic evidence review indicated a consistent reduction in ASCVD events<br />from 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) therapy in secondary and primary prevention populations....</blockquote>However, the new guideline ignored the absence of evidence that statin treatment prolonged life, prevented serious illness overall, or improved health status, function or quality of life.<br /><br />Furthermore, the guideline seemed unreasonably optimistic about the harms of statins.  In particular, it ignored evidence about harms other than diabetes, myopathy (serious muscle disease), and stroke.  Yet there is evidence suggesting that statins at least might cause "liver dysfunction, acute renal failure, and cataracts; cognitive symptoms, neuropathy, and sexual dsyfunction; decreased energy and exertional fatigue; and psychiatric symptoms, including depression, memory loss, confusion, and aggressive reactions" as summarized by Abramson and colleagues. <br /><br />Thus the new guidelines did not make a new and improved case that statin treatment for primary prevention has benefits that outweigh its harms.  One could argue that this is their fatal flaw and thus all the rest of the guidelines' discussion about which patients should get primary prevention was pointless.<br /><br />Dr Abramson and his co-author, Dr Rita Redberg, did get to repeat their arguments about why statin use for primary prevention is not justified in a NY Times <a href="http://www.nytimes.com/2013/11/14/opinion/dont-give-more-patients-statins.html">op-ed,</a> but otherwise the fundamental problem with the guideline's argument for aggressive use of statins went unnoticed.<br /><br /><b>Evidence Supporting Making Decisions about Statin Treatment as Primary Prevention According to Patients' Risks of Developing Atherosclerotic Cardiovascular Disease</b><br /><br />The guidelines suggested statin therapy for patients judged to have at least a 7.5% risk of ASCVD.  As noted above, there is no evidence that statin therapy in primary prevention in general increases survival, reduces serious events overall, improves health status, quality of life, or function, or has benefits that clearly outweigh its harms.  I could not find any reference in the guidelines to clear evidence about the effects of statin treatment in primary prevention for this sub-group of patients.  <br /><br />In the supplemental guideline on risk assessment,(3) there was this  <br /><br /><blockquote class="tr_bq">After deliberation, the Work Group endorsed the existing and widely employed paradigm of matching the intensity of preventive efforts with the individual’s absolute risk.. The Work Group acknowledges that <i>none of the risk assessment tools or novel risk markers examined in the present document have been formally evaluated in randomized controlled trials of screening strategies with clinical events as outcomes.</i></blockquote><br />The wording is confusing, but might be stating that a strategy of using statins only for patients predicted to have a risk greater than 7.5% has not been assessed in a clinical trial.  (It might also, however, be stating that the specific method recommended by the guideline to assess this risk has never been tested in a clinical trial, see below.)<br /><br />The apparent lack of evidence in support of the specific strategy advocated by the guideline to use statins for primary prevention in patients whose risk of ASCVD exceeded the designated threshold did not otherwise attract any notice.<br /><br /><b>Evidence Supporting the Ability of Physicians to Assess Risk of ASCVD Accurately Enough to Implement the Recommended Strategy</b><br /><br /><br />The supplemental guideline stated that previously published methods of risk prediction would not be suitable for the new proposed approach,<br /><br /><blockquote class="tr_bq">As part of its deliberations, the Work Group considered previously published risk scores with validation in NHLBI cohort data as 1 possible approach. However, <i>a number of persistent concerns with existing risk equations were identified </i>including nonrepresentative or historically dated populations, limited ethnic diversity, narrowly defined endpoints, endpoints influenced by provider preferences (e.g., revascularizations), and endpoints with poor reliability (e.g., angina and heart failure [HF]). </blockquote><br />Since the recommended strategy requires an estimation of risk, the lack of availability of acceptable risk assessment methods would appear to be another fatal flaw.  However,  <br /><br /><blockquote class="tr_bq">Given the inherent limitations of existing scores,<i> the Work Group judged that a new risk score was needed</i> to address some of the deficiencies of existing scores, such as utilizing a population sample that approaches, to the degree possible, the ideal sample for algorithm development and closely represents the U.S. population.</blockquote><br /><br />So the question now becomes: did the guideline provide sufficient evidence that the new risk prediction tool developed as part of guideline development predicts sufficiently well to be used to make decisions as recommended by the guidelines?<br /><br />Note that developing, validating, and publishing a new risk score normally would be considered to be tasks that are part of research, not guideline development.  Nonetheless, the guideline developers decided to take on these tasks as part of guideline development, which precluded independent publication of the the results of this research after peer review.  This makes it more difficult for others to critically evaluate the results of the research concerning the new risk score.  But let me attempt to do so. <br /><br />The work group went ahead to develop a new multivariate prediction model for ASCVD.  This means they used statistical methods to find variables, that is, patients' clinical or demographic characteristics, that independently could predict the outcome of interest, and then combined these variables in an equation (or algorithm) to make risk predictions for individual patients.  Such multivariate models to make diagnoses or, as in this case, prognostic predictions have been the subject of considerable research since at least the 1970s.  However, they have not been as useful as their initial advocates hoped.<br /><br />The issues turn out to be a bit complex.  I must digress into an area in which I previously did research.<br /><br />It is quite easy to develop multivariate diagnostic or prediction models.  The statistical analytic tools can almost always find multiple patient characteristics that independently correlate with the outcome of interest.  The problem is that such correlations can be based on random associations, or biases produced by idiosyncrasies in the particular data set used for model development.  That a new model can diagnose or predict accurately for patients who were not in the original data set thus is not assured, and should be considered to be merely a hypothesis.<br /><br />Models developed on one group of patients often do not work when tried prospectively on new patients, probably because the initial development group was somehow not completely representative of all the patients of interest.  For example, a model may have been developed using patients from a particular hospital which attracts different sorts of patients than found in other hospitals in which the model might be used.  .Therefore, before one has confidence in such a multivariate model, one must verify that the model predicted or diagnosed well not only in the group of patients from which it was derived, but prospectively on other patients like those on whom it would be used in clinical practice.<br /><br />The supplemental guidelines did assert that the new model was prospectively tested,<br /><br /><blockquote class="tr_bq"> The equations were also assessed in external validation studies using data from other available cohorts</blockquote><br />However, it did not specify what these cohorts were.<br /><br />There is some data buried in Appendix 4 of the supplemental guideline on the performance of the model.  They did not distinguish results from derived from prospective validation from those from model derivation.<br /><br /><blockquote class="tr_bq"> In summary, discrimination and calibration of the models were very good. C statistics ranged from a low of 0.713  (African-American men) to a high of 0.818 (African-American women). Calibration chi-square statistics ranged from a low of 4.86 (nonHispanic White men) to a high of 7.25 (African-American women).</blockquote><br />These two sentences do not provide strong evidence that the model would predict well when used prospectively.<br /><br />The C-statistic is an overall measure of the ability of the model to discriminate between patients who will go on to develop the diseases of interest and those who will not.  The statistic is formally equal to the probability that were two patients, one who developed disease, and another who did not, selected randomly, the model would predict disease more strongly for the patient who actually got it.  Thus, at best, for 20% of random pairs of African-American women, one who got disease, one who did not, the model would give a more pessimistic prediction for the women who would not get disease.  This is good, but not great discrimination ability.  (If this result referred to data from model derivation, not prospective validation, it is likely to be over-optimistic.) <br /><br />Furthermore, since the guideline would be used to make decisions based on the absolute risk, its calibration is also important.  Calibration is the measure of whether the model predictions of risk are close to reality.  To assess calibration, one ought to assess the whole range of predictions made by the model.  Given that the guidelines suggest a 7.5% risk threshold, it would be particularly important to determine whether patients given predictions above and below that value really have risks above and below that value.<br /><br />Unfortunately, the two sentences above are not helpful in this regard.  The chi-square statistic presented is a measure of overall calibration, but does not show calibration for groups of patients given predictions with particularly interesting values, like above or below 7.5%<br /><br />Note that the supplemental guideline on risk assessment includes a statement that details about the model validation done "internally and externally" are in a <a href="http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a/suppl/DC1">Full Panel Report Data Supplement</a>.  The download of that supplement so far does not seem to work<br /><br />Setting that aside for a moment, the published guidelines do not provide good evidence that the risk prediction tool the guidelines recommend should be used to assess ASCVD risk in order to make decisions on statin use for individual patients in primary prevention. The lack of a sufficiently accurate method to predict risk seems to a fatal flaw for a strategy that requires risk prediction.<br /><br /><u>Controversy in the Media </u><br /><br />It turns out that I was not the first person to identify this problem. In fact, it appears that during the internal review process for the guidelines, major questions had already been raised about the risk prediction model's calibration. However, these questions did not seem to have been conveyed to the guideline authors, and hence were never addressed. <br /><br />As <a href="http://www.nytimes.com/2013/11/18/health/risk-calculator-for-cholesterol-appears-flawed.html">reported</a> by the New York Times on November 17, 2013,<br /><br /><blockquote class="tr_bq">The problems were identified by two Harvard Medical School professors whose findings will be published Tuesday in a commentary in The Lancet, a major medical journal. The professors, Dr. Paul M. Ridker and Dr. Nancy Cook, <i>had pointed out the problems a year earlier </i>when the National Institutes of Health’s National Heart, Lung, and Blood Institute, which originally was developing the guidelines, sent a draft to each professor independently to review. Both reported back that the calculator was not working among the populations it was tested on by the guideline makers.<br /><br />That was unfortunate because the committee thought the researchers had been given the professors’ responses, said Dr. Donald Lloyd-Jones, co-chairman of the guidelines task force and chairman of the department of preventive medicine  at Northwestern University.</blockquote><br />The article by Ridker and Cook was indeed published. on November 19, 2013(4).  It suggested major problems with the calibration of the risk assessment model, <br /><br /><blockquote class="tr_bq"><i>Another concern for clinicians is whether the new prediction algorithm created by the ACC/AHA correctly assesses the level of vascular risk. To be useful, prediction models must not only discriminate between individuals with and without disease, but must also calibrate well so that predicted risk estimates match as closely as possible the observed risk in external populations</i>. We calculated predicted 10-year risks of the same atherosclerotic events using the new ACC/AHA risk prediction algorithm and compared these estimates with observed event rates in three large-scale primary prevention cohorts, the Women's Health Study, the Physicians' Health Study, and the Women's Health Initiative Observational Study. <br /><br />As shown in figure 1, in all three of these primary prevention cohorts,<i> the new ACC/AHA risk prediction algorithm systematically overestimated observed risks by 75–150%, roughly doubling the actual observed risk. </i>As shown in figure 2, <i>similar overestimation of risk was observed in two external validation cohorts used by the guideline developers themselves, an issue readily acknowledged in the report</i>. Thus, on the basis of data from these five external validation cohorts, i<i>t is possible that as many as 40–50% of the 33 million middle-aged Americans targeted by the new ACC/AHA guidelines for statin therapy do not actually have risk thresholds that exceed the 7·5% threshold suggested for treatment.</i> Miscalibration to this extent should be reconciled and addressed in additional external validation cohorts before these new prediction models are widely implemented. It is possible, for example, that the five external validation cohorts are more contemporary than the cohorts used in the risk prediction algorithm and thus reflect secular improvements in overall health and lifestyle patterns in the USA over the past 25 years. </blockquote><br />Note that Figure 1 of the Ridker and Cook article showed the calibration of the model in the patient cohorts newly tested by these authors, focusing in particular on whether patients predicted to have risks of cardiovascular disease just over the 7.5% threshold actually had rates of such disease greater than 7.5%.  They clearly did not   Note also that Figure 2 showed calibration of the model when the guideline authors attempted to test it on new patient cohorts, apparently the data found in the so far inaccessible Full Panel Report Data Supplement.  Again, the model overestimated risk for patients just over the crucial threshold.<br /><br />So the guideline developers knew that their model overestimated risk, buried this information in supplemental data, did not admit or perhaps appreciate how it threatened the credibility of their guidelines, and somehow were not given the internal review that suggested this was a fatal flaw of the proposed guidelines .  <br /><br /><b>The Guideline Developers' Responses</b><br /><br />The media controversy over the accuracy of the prediction model incorporated into the new guidelines provoked responses from the guideline developers, but these responses were at best confused.  .   <br /><br />First, as reported by the NY times,<br /><br /><blockquote class="tr_bq">In a response on Sunday, Dr. [Sidney C] Smith of the guidelines committee said the concerns raised by Dr. Cook and Dr. Ridker 'merit attention.'<br /><div itemprop="articleBody"><br />But, he continued, '<i>a lot of people put a lot of thought into how can we identify people who can benefit from therapy</i>.' Further, said Dr. Smith, who is also a professor of medicine at the University of North Carolina and a past president of the American Heart Association, '<i>What we have come forward with represents the best efforts of people who have been working for five years</i>.'</div></blockquote><div itemprop="articleBody"><br /></div><div itemprop="articleBody">Note that this response includes two logical fallacies.  First, it contained a <a href="http://www.nizkor.org/features/fallacies/straw-man.html">straw man argument</a>.  It appeared to respond to accusations no one made.  Nobody accused the guideline developers of being lazy, not putting in much effort, or not devoting much thought to the effort.  The response also included an implied <a href="http://www.nizkor.org/features/fallacies/appeal-to-authority.html">appeal to authority</a>: big experts came up with these guidelines so their opinions should be credited, even in the presence of data to the contrary.   </div><div itemprop="articleBody"><br /></div><div itemprop="articleBody">Also, as <a href="http://www.cnn.com/2013/11/18/health/cholesterol-calculator/">reported</a> by CNN,</div><blockquote class="tr_bq"><div class="cnn_storypgraphtxt cnn_storypgraph9">However, 'I can't speak to whether the calculator is valid or not,' Dr. Robert Eckel, co-chair of the American Heart Association committee that wrote the new guidelines and the association's past president, told CNN. 'That needs to be determined.'</div><div class="cnn_storypgraphtxt cnn_storypgraph9"><br /></div><div class="cnn_storypgraphtxt cnn_storypgraph10">'<i>We trusted that the calculator worked,' </i>he said. <i>'We trusted that the calculator is valid.'</i></div></blockquote><div class="cnn_storypgraphtxt cnn_storypgraph10"><br /></div><div class="cnn_storypgraphtxt cnn_storypgraph10">This was confusing.  Maybe Dr Eckel meant it to be another appeal to authority, the authority in question being that of the work group that developed the risk prediction model.  </div><div class="cnn_storypgraphtxt cnn_storypgraph10"><br /></div><div class="cnn_storypgraphtxt cnn_storypgraph10">Furthermore, again according to CNN,</div><div class="cnn_storypgraphtxt cnn_storypgraph10"><br /></div><blockquote class="tr_bq"><div class="cnn_storypgraphtxt cnn_storypgraph10">Researchers apparently did not receive the professors' responses, Dr. Donald Lloyd-Jones, chairman of the committee that developed the equation, told the Times.</div><div class="cnn_storypgraphtxt cnn_storypgraph10">  </div><div class="cnn_storypgraphtxt cnn_storypgraph18">But Lloyd-Jones told reporters Monday, '<i>There's nothing wrong with these equations.</i>'</div><div class="cnn_storypgraphtxt cnn_storypgraph18"><br /></div><div class="cnn_storypgraphtxt cnn_storypgraph19"><i>Committee members were aware there could be 'overestimation of risk in some populations,' </i>he said.</div></blockquote><div class="cnn_storypgraphtxt cnn_storypgraph19"><br /></div><div class="cnn_storypgraphtxt cnn_storypgraph19">In addition,</div><div class="cnn_storypgraphtxt cnn_storypgraph19"><br /></div><blockquote class="tr_bq"><div class="cnn_storypgraphtxt cnn_storypgraph19"> 'Our risk assessment guideline <i>doesn't tell you what to do</i>. ... <i>It just evaluates risk,</i>' he said.</div></blockquote><div class="cnn_storypgraphtxt cnn_storypgraph19"><br /></div><div class="cnn_storypgraphtxt cnn_storypgraph19">I am not sure this even rises to the level of a logical fallacy.  It appears to be pure denial.  The whole point of the risk assessment tool was to determine whether a patient's risk is above or below the thresholds suggested by the treatment guideline, and thus to tell you what to do.  There clearly is something wrong with "these equations."  Using them appears to vastly overestimate risk, and thus implementation of the guideline would probably lead to vast over treatment of real people  . </div><div class="cnn_storypgraphtxt cnn_storypgraph19"><br /></div>Thus, after promulgating guidelines that seemed hardly based on evidence, when challenged, the guideline developers' response was confused and illogical.    <br /><br /><u>What About the Issue of Benefits versus Harms? </u><br /><br />The other problems that I identified above, lack of evidence that primary prevention provides benefits that clearly outweigh harms, and lack of evidence that a strategy based on risk assessment would provide benefits that outweighs harms, did not get media coverage, and so did not provoke a response from the developers.  However, I  did find that one of the members of the guideline panel implied her approach to the benefits versus harms issue in a Medscape news <a href="http://www.medscape.com/viewarticle/814526">article</a>.   Dr Noel Bairey Merz gave a talk at the 2013 American Heart Association meeting about primary prevention for women, first saying<br /><br /><blockquote class="tr_bq">Although the randomized clinical trial evidence supporting primary prevention with statin therapy in women is not perfect, 'the absence of data means negative data.'<br /><br />That is the argument formulated by Dr Noel Bairey Merz (Cedars Sinai Medical Center, Los Angeles, CA), who spoke today here at the American Heart Association 2013 Scientific Sessions.  <b> </b> <br /><br />'How confident are we that statins do not save lives in the week before a heart attack, but they do save lives the week after a heart attack, for women and men?'</blockquote><br />Also,<br /><br /><blockquote class="tr_bq">in the overall JUPITER study of 18 000 patients, there was no treatment benefit when women were studied as a subgroup. Merz argues that JUPITER is powered for the total sample size only, not for women alone. In addition, the statistical test for heterogeneity revealed the interaction by sex was not statistically significant.<br /><br />'Pretty much all the subgroups fall beyond the statistically significant range,' said Merz. 'So should we withhold treatment for women, who now are the majority of victims of cardiovascular disease, because of low precision and a trial that was not designed to address or answer this question?'</blockquote><br />So Dr Merz seemed to assume that statins work for particular patients in the absence of evidence that they do not work, maybe implying a general assumption that all treatments are beneficial until proven otherwise.  This stands a central precept of evidence-based medicine, and perhaps the ancient dictum to physicians to do no harm, on their heads.<br /><br /><br /><div class="cnn_storypgraphtxt cnn_storypgraph19"><b>Unwarranted Enthusiasm for (Over) Treatment and Conflicts of Interest</b><br /><br />The new cholesterol guidelines, and those who developed them, seem enthused about the treatment of cholesterol with statin drugs for primary prevention in the absence of evidence that such treatment produces benefits that outweigh its harms.  They also seem enthused about basing treatment decisions on a statistical prognostic model that has not been shown to be accurate, and in fact which appears to be biased towards promoting excess treatment in the context in which it would be used.   The excess enthusiasm occurred in spite of evidence, and at times in spite of logic.<br /><br /> One possible reason that the guideline developers got so enthused that they seemed unable to think straight appears to be their own conflicts of interest, as first publicly noted in a <a href="http://www.pharmalive.com/cholesterol-guidelines-panelists-and-their-conflicts-of-interest">post</a> on Pharmalot. Reviewing the disclosure forms provided with the guidelines revealed more detail.<br /><br />Of the 13 people on the main treatment guideline panel who were not NHLBI staffers serving ex-officio, 7 had financial relationships with pharmaceutical companies that manufacture statins:<br /><br />- Jennifer Robinson, co-chair, research funded by <i>AstraZeneca</i> and <i>Merck</i>;<br />- C Noel Bairey Merz, consulting for <i>Abbott, Bristol-Myers Squib Novartis,</i> and <i>Pfizer</i>;<br />- Robert H Eckel, consulting for <i>Merck, Pfizer </i>and <i>Abbott;</i> <br />- Anne Carol Goldberg, consulting for <i>Abbott</i> and <i>Merck</i>, research funded by <i>Abbott, Merck</i>, and Novartis;<br />- J Sanford Schwartz, consulting for <i>Abbott, Merck</i> and<i> Pfizer</i>, research funded by <i>Pfizer</i>;<br />- Karol Watson, consulting for <i>Abbott, AstraZeneca, Merck</i> and <i>Pfizer,</i> research funded by <i>Merck</i>;<br />- Peter W F Wilson, consulting for and research funded by <i>Merck</i>.<br /><br />Of the 10 expert reviewers for this panel, 3 had financial relationships with pharmaceutical companies that manufacture statins<br />-  William Virgin Brown, consultant for <i>Abbott, Bristol-Myers Squibb</i>, and <i>Pfizer</i>;<br />-  Matthew Ito, consultant for <i>Kowa</i>;<br />- Robert S Rosenson, consultant for <i>Novartis</i> and <i>Pfizer</i>. <br /><br />Of the 11 people on the risk prediction panel who were not NHLBI staffers serving ex-officio, 5 had financial relationships with pharmaceutical companies that manufacture statins<br />-David C Goff Jr, co-chair, research funded by<i> Merck</i>;<br />- Raymond Gibbons, consultant for <i>AstraZeneca;</i><br /><br />- Jennifer Robinson, research funded by <i>AstraZeneca</i>, and <i>Merck</i>;<br />- J Sanford Schwartz, consulting for <i>Abbott, Merck </i>and <i>Pfizer,</i> research funded by <i>Pfizer</i> [although these relationships were not listed as relevant to this panel, but found in the listing for the panel above];<br />- Peter W.F Wilson, consultant for and research funded by <i>Merck</i>.<br /><br />Also, in the Abramson and Redberg NY Times op-ed, the authors noted<br /><br /><blockquote class="tr_bq">both the American Heart Association and the American College of Cardiology, while nonprofit entities, are <i>heavily supported by drug companies </i></blockquote><br />As noted on Pharmalot, the prevalence of conflicted panel members did not appear to conform to the <a href="http://www.iom.edu/Activities/Quality/ClinicPracGuide.aspx">standards for the development of trustworthy guidelines</a> recently published by the Institute of Medicine:<br /><br /><blockquote class="tr_bq">whenever possible, <i>guideline development group members should not have conflicts of interest</i>… and <i>the chair or co-chairs should not be a person(s) with conflicts of interest.</i></blockquote><br />Also, <a href="http://www.latimes.com/science/sciencenow/la-sci-sn-statins-risk-calculator-wrong-20131118,0,3734255.story">noted</a> by the Los Angeles Times was this comment from Dr John Abramson, lead author of the commentary on statins in primary prevention(4),<br /><br /><br /><blockquote class="tr_bq">'There is overtreatment that’s been built into the risk calculator, and this is a warning sign about the overtreatment that’s built into the guidelines themselves and the conflicts of interest in the organizations that are overseeing the production of these guidelines,' said Dr. John Abramson, a Harvard University cardiologist who has argued that statins offer little value for people with a 10-year risk level of heart attack or stroke of less than 20%. 'There aren’t brakes being put on the enthusiasm and overreaching of the experts.'<br /><br />'<i>There are statin believers, and when you hear these experts talk, they’re talking emotionally, not scientifically,</i>' Abramson added. '<i>The experts are using emotion, not science.</i>'</blockquote><br />As Joe Collier  observed, "people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult."(5)<br /><br />This difficulty giving clear advice, when amplified by a guideline for a common problem supported by prestigious non-profit organizations, and promoted by vigorous public relations, could lead to "more than 45 million middle-aged Americans who do not have cardiovascular disease being recommended for consideration of statin therapy" (per Ridker and Cook[4]) unnecessarily, likely resulting in millions suffering unneeded side effects, and billions in costs.   <br /><br /><b>Summary</b><br /><br />Guidelines for management of a very common problem promulgated by a major medical society and a major disease oriented non-profit organization suggested a strategy that would vastly increase drug treatment of currently healthy patients.  The strategy appears not to have been based on good evidence.  When some of the problems with this evidence were pointed out, the guideline developers responded with illogic.  Apparently many of the guideline developers have financial relationships with the drug companies that would most profit from increases in drug treatment as recommended by the guidelines  Implementation of the new guidelines might results in millions of people in the US receiving unneeded drugs, with resultant side effects and costs. .<br /><br />Do we need more examples of how conflicts of interest are causing the poor outcomes and excess costs that are wrecking our health care system?  Do we need more excuses not to eliminate conflicts of interest from guideline development?  Do we need more delay implementing the standards provided by the Institute of Medicine report on trustworthy guidelines?  Do we need more excuses not to drastically reduce conflicts of interest affecting academic medicine, medical societies, and disease specific non-profits, specifically starting with the earlier (and so far generally disregarded) Institute of Medicine <a href="http://www.iom.edu/Reports/2009/Conflict-of-Interest-in-Medical-Research-Education-and-Practice.aspx">report on conflicts of interest in medicine</a>?<br /><br />While we in the US argue incessantly in the details of minor reforms of our supposed free health care market, we ignore the rot at its foundations.  True health care reform would attack the conflicts of interest that have put money, not patients at the center of health care. <br /><br /></div><br /><b>References</b><br /><br />1.  Stone NJ, Robinson J, Lichtenstein AH,  et al.  2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation 2013.  Link <a href="http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a">here</a>.<br />2.  Abramson JD, Rosenberg HG, Jewell N et al.  Should statins be prescribed to people at low risk of cardiovascular disease. Brit Med J 2013; 347: 15-17.  Link <a href="http://www.bmj.com/content/347/bmj.f6123">here</a>.<br />3.  Goff Jr DC, Lloyd-Jones DM, Bennett G, et al.  2013 ACC/AHA Guideline on the Assessment of Cardiovascular<br />Risk.  Journal of the American College of Cardiology (2013), doi: 10.1016/j.jacc.2013.11.005.  Link <a href="http://content.onlinejacc.org/data/Journals/JAC/0/11005.pdf">here</a>.<br />4.  Rikder PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease.  Lancet 2013;   Link <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2962388-0/fulltext">here</a>.<br />5.   Collier J. The price of independence. Br Med J 2006; 332: 1447-9.  Link <a href="http://bmj.bmjjournals.com/cgi/content/full/332/7555/1447">here</a><br /><!--7--><!--7--><br />

Confused Thinking about New Cholesterol Guidelines - Were Conflicts of Interest to Blame?

For years, clinical practice guidelines promulgated by prominent health care organizations have been hailed with accolades as received wisdom.  However, there is increasing reason to be skeptical of s…

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WHEN IS DISCLOSURE NOT DISCLOSURE?

<br /><br /><div class="MsoNormal">WHEN IS DISCLOSURE NOT DISCLOSURE? <o:p></o:p><br /><br /></div><div class="MsoNormal">Hint: When it is made by the Chairman of the DSM-5 Task Force.<o:p></o:p><br /><br /></div><div class="MsoNormal">Here is a case study in conflict of interest (COI). A remarkable <a href="http://archpsyc.jamanetwork.com/article.aspx?articleID=1780020&utm_source=Silverchair%20Information%20Systems&utm_medium=email&utm_campaign=JAMAPsychiatry%3AOnlineFirst11%2F20%2F2013">confession</a> has just appeared by a group of 5 prominent academics, writing in the journal JAMA Psychiatry. Having been outed to the Editors, they now admit to concealing pertinent financial information. One of the five is David J. Kupfer, MD, chairman of the DSM-5 Task Force and past chairman of the department of psychiatry at The University of Pittsburgh. The others are from Pittsburgh, Minnesota, and Chicago.<o:p></o:p><br /><br /></div><div class="MsoNormal">With millions in funding from NIMH, these folks have been developing new approaches to testing for anxiety and depression. The technical details are not important for this story. What matters is that they have clearly set their sights on a large market for diagnostic screening, epidemiological research, and clinical practice. They have recently published promotional reports talking up three products and projecting major applications – but before taking care of the nuts and bolts of scale development.<o:p></o:p><br /><br /></div><div class="MsoNormal">Their major <a href="http://archpsyc.jamanetwork.com/article.aspx?articleid=1389370">report</a> in JAMA Psychiatry contained a disclosure to the effect that they might at some time in the future consider commercial development of their depression scale. This disclosure was phony. We now know that, in lieu of frankly disclosing a major COI, they opted for a disingenuous, dissembling statement that was economical with the truth.<o:p></o:p><br /><br /></div><div class="MsoNormal">I thought the content of their report was sub-par, and the journal published a <a href="http://archpsyc.jamanetwork.com/article.aspx?articleid=1707797&resultClick=3">letter</a> from me to that effect. They <a href="http://archpsyc.jamanetwork.com/article.aspx?articleid=1707798&resultClick=3">responded</a> to my criticism with hand waving, and they tried to impugn me for bias related to my own (disclosed) COI. This foolish, <i>ad hominem</i> tactic aimed to divert attention from the substance of my critique – for which they had no adequate response.<o:p></o:p><br /><br /></div><div class="MsoNormal">As I am not a person who suffers fools or insults gladly, their evasive response caused me to do some checking. I quickly learned that the gang of five are shareholders in a private corporation. Before their paper was accepted by JAMA Psychiatry, the corporation was incorporated in Delaware and soon after registered to do business in Illinois. Those facts were not disclosed in the original report or in the published letter of Reply to me. These omissions were acknowledged in the notice of Failure to Report that appeared on-line today.<o:p></o:p><br /><br /></div><div class="MsoNormal">It gets worse. Other things that I learned – and that I communicated to the journal – make it clear that the corporate train had left the station in advance of the letter of Reply. For instance, a professional operations and management executive (Mr. Yehuda Cohen) had joined the corporation. He had established the corporate <a href="http://www.adaptivetestingtechnologies.com/">website</a>, where he was featured as a principal, along with the gang of five. The website also displayed a professionally crafted Privacy Policy, dated ahead of the letter of Reply. This document identified what appears to be a commercial business address for the corporation. The notice of Failure to Disclose is silent on these facts.<o:p></o:p><br /><br /></div><div class="MsoNormal">So, the published notice of Failure to Disclose still withholds pertinent information, which makes a mockery of the weasel words that they have not released any tests for commercial or professional use. Not yet, they haven’t. But they are under way, make no mistake. This prevarication creates the impression of a habitual lack of transparency. Considering that I gave the journal all this information, one has to be surprised that JAMA Psychiatry went along with this prevarication. Plus, would it have killed them to apologize for their foolish attempt to smear me, as I requested? In correspondence with me, the Editor in Chief of JAMA didn’t want to go there, and he refused to publish my letter that detailed the facts, citing the most specious of grounds. The Editor of JAMA Psychiatry has ducked for cover when I faulted him for publishing the <i>ad hominem</i> material in the first place.<o:p></o:p><br /><br /></div><div class="MsoNormal">This deplorable episode casts a pall on the repeated assurances by Dr. Kupfer that COI issues were <a href="http://www.medscape.com/viewarticle/777132">under control</a> in the DSM-5 process. If the chairman of the DSM-5 Task Force doesn’t have his own act together, then what are his assurances worth? The new instruments proposed by this corporation bear an eerie resemblance to cross-cutting dimensional measures that were promoted for DSM-5 but that didn’t make the final cut. As far as I know, Dr. Kupfer didn’t declare his interest in this corporation for scrutiny <i>vis à vis</i> DSM-5.<o:p></o:p><br /><br /></div><div class="MsoNormal">Another lesson is that even Failure to Report notices can be weasel documents. I fault the Editors of JAMA Psychiatry, Joseph Coyle, MD, and of JAMA, Howard Bauchner, MD, for the non-rigorous standard they applied to the notice of Failure to Disclose. They acquiesced in another dissembling response.<o:p></o:p><br /><br /></div><div class="MsoNormal">Yet another lesson is that all authors are accountable for the accuracy of disclosure statements. Some of these authors might claim they relied on the lead author and president of the corporation, Robert Gibbons, PhD, a statistician at The University of Chicago, to make sure everything was kosher. Big mistake – just like the infamous case of the Nemeroff-led Cyberonics – vagus nerve stimulation<a href="http://hcrenewal.blogspot.com/2006/08/money-and-medical-journals.html"> review</a> that failed to disclose that the academic authors (ahem) were paid consultants of the corporation. When your name is on the byline, be sure you cover the bases for your own protection, and don’t squawk when you are called out.<br /><br /><o:p></o:p></div><div class="MsoNormal">Finally, where is NIMH in all of this? Since when are public NIMH funds to be treated as commercial seed money? Who actually owns the algorithms and data bases on which the Gibbons corporation relies for its commercial aspirations? Why are they not publicly accessible? Is Thomas Insel on top of this?<o:p></o:p></div><div class="MsoNormal"><br /></div><br /><div class="MsoNormal"><br /></div>

WHEN IS DISCLOSURE NOT DISCLOSURE?

WHEN IS DISCLOSURE NOT DISCLOSURE? Hint: When it is made by the Chairman of the DSM-5 Task Force.Here is a case study in conflict of interest (COI). A remarkable confession has just appeared by a grou…

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