GlaxoSmithKline's Marketing Firm Promised "Clinical Trials Could be Your Solution" to Poor Graduate Students

We have frequently raised concerns about the increasing domination of clinical research, particularly clinical trials, by those with vested in interests in the research producing particular results.  In particular, drug, biotechnology and device companies often sponsor trials meant to evaluate their own products.  Often it appears that commercial trial sponsors <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulate</a> various aspects of research design, implementation, analysis, and dissemination to increase the likelihood of a result favorable to their interests.  Furthermore, when even such manipulation fails to produce the desired result, particular studies may simply be <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppressed</a>, that is, hidden.<br /><br /><b>Clinical Trial Participation as "Your Solution" to Graduate Students' Money Woes </b><br /><br />A recent story, first told on the In-Pharma Technologist web site, gave an example of how trial recruitment could be gamed so as to produce more compliant study subjects. Since that web-site does not allow copy and pasting of even a few sentences of its content, I will quote, instead, from a subsequent <a href="http://www.theguardian.com/money/2014/jun/22/glaxosmithkline-gsk-interns-drug-trial-pitch">article in the Guardian</a>.<br /><br /><blockquote class="tr_bq">GlaxoSmithKline  the pharmaceuticals multinational, has apologised after being accused of playing on the hardship of unpaid interns to recruit them to take part in clinical trials.<br /><br /><i>A marketing firm working for the FTSE 100 company sought to place a blog on careers advice websites boasting that involvement in drug trials could help graduates to finance their way through unpaid work placements</i>.<br /><br />In a proposed 'guest blog' for the website <a href="http://graduatefog.co.uk/2014/3433/unpaid-interns-targeted-for-clinical-trials/" title="">Graduate Fog</a>, an employee at TouchPoint Digital, working on behalf of GSK, wrote: 'Clinical trials could be your solution.'</blockquote><br />The "guest blog" proposed that many graduate students "would prefer an immediate income to tide you over for the coming months."  So,<br /><br /><blockquote class="tr_bq"><i>Clinical trials could be your solution. Depending on the length of the study, you could earn up to £2,000 per trial for up to 4 trials a year</i>, plus reasonable travel expenses.</blockquote><br />This was not a one-off,<br /><br /><blockquote class="tr_bq"> Touchpoint provided examples of similar articles previously published on websites targeted at students. In an <a href="http://graduatefog.co.uk/2014/3433/unpaid-interns-targeted-for-clinical-trials/" title="">email to the founder of Graduate Fog, Tanya de Grunwald</a>, it added: 'Your readers would also benefit if there is a small link at the end of the article to the GSK website, which is the biggest pharmaceutical company in the UK, so that if they want to find out more or get answers to more specific questions they can do so.'</blockquote><br /><b>Excessive Inducement </b><br /><br />The story was <a href="http://blogs.wsj.com/pharmalot/2014/06/23/glaxo-dumps-firm-for-praying-on-college-grads-for-clinical-trials/">picked up by Ed Silverman at the PharmaLot blog</a> in the US, who pointed out how TouchPoint Digital appeared to be supplying an excessive inducement to vulnerable subjects,<br /><br /><blockquote class="tr_bq">Tanya de Grunwald, who runs the Graduate Fog website in the U.K., objected to the tone of the overture. 'Some of my readers are feeling very low, vulnerable and desperate for money,' she wrote us in an e-mail after openly questioning the recruiting tactic in <a data-ls-seen="1" href="http://graduatefog.co.uk/2014/3433/unpaid-interns-targeted-for-clinical-trials/">a note to readers</a> on her website last week. 'Many are unemployed. Others are in low-paid graduate jobs or doing unpaid internships.'<br /><br />'Suggesting that participating clinical trials is a great way to earn easy cash is not just crass – I think it’s irresponsible. Surely, <i>the more desperate someone is for money, the more likely they are to be dazzled by the financial benefits and less careful about weighing up the risks</i>.'</blockquote><br />A long time ago, that is, from 2006 - 2008, we published a series of posts about how <a href="http://hcrenewal.blogspot.com/search/label/contract%20research%20organizations">contract research organizations</a> running clinical research projects for commercial health care firms often preyed on financially and otherwise vulnerable research subjects by offering what would appear to such people to be dazzling remuneration.  For example, we discussed the trials by SFBC International (later PharmaNet Development Group, and now apparently <a href="http://www.inventivhealthclinical.com/">Inventiv Health Clinical</a>)  in Miami that enrolled immigrants, often undocumented, under questionable circumstances and in Montreal that resulted in the transmission of active tuberculosis (see post <a href="http://hcrenewal.blogspot.com/2006/03/consequences-of-sfbc-internationals.html">here</a> and links backward); and the trial by <a href="http://www.parexel.com/">Parexel International </a>in London that put most of its subjects in intensive care (see post <a href="http://hcrenewal.blogspot.com/2006/08/parexel-blues-again.html">here</a>, with links backward). In 2008, as we discussed <a href="http://hcrenewal.blogspot.com/2008/06/clinical-trials-torture-economy.html">here</a>, two articles questioning the ethics of research done under the auspices of CRO appeared in two major medical journals.  Excessively zealous recruiting designed to tempt vulnerable subjects with money appears unethical, and may be dangerous for these subjects.<br /><br /><b>How Excessive Inducement Could Lead to Invalid Trial Results</b><br /><br />Not only is such a practice apparently unethical and dangerous, it could endanger patients outside the research projects in question by producing invalid research.  Subjects who could be dazzled by such inducements might avoid disclosing conditions which would otherwise exclude them from particular research projects, or participate in multiple projects without sufficient or any wash out periods in between, meaning that one treatment's effects could confound another.  (Note that the blog post proposed by the marketer above suggested that subjects could participate in multiple trials during one year.)  Furthermore, subjects desperate to complete studies and earn their fees might avoid reporting adverse effects to avoid the risk of premature termination of their participation, or avoid protesting questionable actions by the researchers.    <br /><br />But now in the modern era of the Internet and social media, overzealous recruitment using monetary lures is still going on.  As per PharmaLot,<br /><br /><br /><blockquote class="tr_bq">One expert believes the flap is not surprising, because <i>drug makers are under pressure to maintain a steady stream of clinical trial recruits.</i><br /><br /> 'Middle class folks just sit back and wait until the drug reaches the market. <i>Poor folks are the guinea pigs in an economy that is more and more uneven, and uncertain by the day</i>,' says Roberto Abadie, a senior researcher at the Social Networks Research Group at John Jay College, City University of New York, and author of ‘The Professional Guinea Pig: Big Pharma and the Risky World of Human Subjects.' </blockquote><br /><b>A Belated Response from GSK </b><br /><br />Apparently only after the story broke did GSK notice there was a problem.  Again, per PharmaLot,<br /><br />A Glaxo spokeswoman <i>blamed the outside marketing firm</i> for the episode. In an e-mail, she wrote us that 'we would agree that the tone used in the ads… is wrong. It trivializes the role of clinical trials in developing new medicines and the part that volunteers play in that process. This isn’t acceptable and we’re looking into what happened.'<br /><br />Whether GSK was properly supervising the marketing firm, and whether GSK had provided incentives that might have lead to overzealous recruitment were not addressed. <br /><br /><b>Summary</b><br /><br />This story is yet another reminder that health care professionals, health policy makers, and the public at large should be extremely skeptical of clinical research sponsored (and controlled) by those with vested interests in the research results turning out a certain way, particularly clinical trials run by drug, biotechnology, or biotechnology companies meant to assess those companies' own products. However, note that very rarely do published clinical trial reports provide enough detail about subject recruitment to determine whether overzealous recruitment and undue inducements may have lead to enrollment of subjects who should have been excluded, under reporting of adverse effects, etc.<br /><br />In my humble opinion, we need to reassess current policies that allows organizations with such obvious conflicts of interest to run experiments on human beings (which is what clinical trials are.)<br /><br />By the way, this story is also a reminder that most big drug, device and biotechnology firms seem to be associated again and again with dodgy clinical research.   For example, see what we have previously written about GSK<a href="http://hcrenewal.blogspot.com/search/label/GlaxoSmithKline"> here</a>. <br /><br />

GlaxoSmithKline's Marketing Firm Promised "Clinical Trials Could be Your Solution" to Poor Graduate Students

We have frequently raised concerns about the increasing domination of clinical research, particularly clinical trials, by those with vested in interests in the research producing particular results.  …

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Fourth Time is the (Anti)Charm? - UK NICE Highlights "Uncertainties in the Evidence Base" About Sovaldi

As we have discussed, (<a href="http://hcrenewal.blogspot.com/2014/04/knee-deep-in-hoopla-triumph-of-medical.html">here</a>, <a href="http://hcrenewal.blogspot.com/2014/05/some-authoritative-skepticism-about.html">here</a> and <a href="http://hcrenewal.blogspot.com/2014/05/sovaldi-revolution-in-clinical-care-or.html">here</a>), while anger continues to build about the $1000/ pill price sought by Gilead for its new antiviral drug for hepatitis C, Sovaldi (sofosbuvir), almost all public discussion still treats the drug as miraculous.  However, my reading of some key trials, and reviews by three groups of evidence-based medicine experts, suggested that the evidence supporting the drug is actually weak and unclear, and hardly suggests it is miraculous.<br /><br /><b>NICE Weighs In </b><br /><br />Now, as first noted by the indomitable Ed Silverman in his revived PharmaLot blog, the National Institute for Health and Care Excellence in the UK is also skeptical.    <br /><br /><blockquote class="tr_bq"> the U.K.’s National Institute for Health and Care Excellence, otherwise known as NICE, has <i>declined to endorse the use of Sovaldi, at least for now</i>, until Gilead supplies further evidence of the medication works in certain subgroups of patients. In announcing the move, NICE officials wrote there are '<i>substantial uncertainties' in the evidence from the drug maker</i>. In <a data-ls-seen="1" href="http://www.nice.org.uk/newsroom/pressreleases/NICEOnDraftGuidanceForSofosbuvirSovaldiDrugHepatitisC.jsp">a statement</a> issued about a draft guidance, NICE wrote that the agency 'is minded not to recommend' that the U.K.’s National Health Service cover the cost of Sovaldi,</blockquote><br />The actual <a href="http://www.nice.org.uk/newsroom/pressreleases/NICEOnDraftGuidanceForSofosbuvirSovaldiDrugHepatitisC.jsp">statement</a> said,<br /><br /><blockquote class="tr_bq"> The available evidence shows that sofosbuvir is an effective treatment for chronic hepatitis C in certain patients. However, evidence is lacking for some subgroups of patients with chronic hepatitis C, and there are also substantial uncertainties in the evidence base presented by the manufacturer. The Committee has therefore requested further information from the manufacturer before it can decide whether sofosbuvir is a cost-effective use of NHS resources.</blockquote><br />In the US, the only other news source that covered the NICE statement was <a href="http://www.businessweek.com/news/2014-06-16/u-dot-k-dot-cost-regulator-may-reject-gilead-s-sovaldi-treatment">Bloomberg</a>.<br /><br /><b>The Problems with the Evidence</b><br /><br />As we discussed in our previous posts, the problems with the evidence underlying Sovaldi include:<br />- Lack of a randomized controlled trial comparing Sovaldi to the previously most recommended treatment regimen<br />- The only trial trial to compare an antiviral regimen containing Sovaldi to one without it  (Sovaldi plus ribavirn versus peg-interferon plus ribavirin) used a lower dose of ribavirin in the comparator regimen, seemingly handicapping it; had a highly selected patient population whose results would be unlikely to generalize to many patients in the real world; had issues with randomization of patients; only assessed short-term "sustained" virologic response, but not any clinical outcomes; even so, did not show that the sofosbuvir containing regimen produced a better SVR than did the comparator; and appeared to show that the sofosbuvir containing regimen produced more severe adverse effects, and perhaps a higher death rate than the comparator regimen<br />-  So far, the other published trials included one versus placebo, and multiple trials that compared only sofosbuvir containing regimens to each other, and hence were effectively just case series of patients receiving sofosbuvir.  These case-series all had highly selected patient populations results from whom would be unlikely to generalize to real world patients.<br /><br />The severe problems with the evidence have now also been noted by<br />-  the <a href="https://www.iqwig.de/en/press/press_releases/press_releases/sofosbuvir_indication_of_added_benefit_for_specific_patients.6099.html">German Institute for Quality and Efficiency in Healthcare</a> (IQWiG)<br />-  the US Institute for Clinical and Economic Review (look <a href="http://archinte.jamanetwork.com/article.aspx?articleid=1867174">here</a>)<br />-  the US Center for Evidence-Based Policy (look <a href="http://hcrenewal.blogspot.com/2014/05/sovaldi-revolution-in-clinical-care-or.html">here</a>) <br />-  the<a href="http://www.nice.org.uk/newsroom/pressreleases/NICEOnDraftGuidanceForSofosbuvirSovaldiDrugHepatitisC.jsp"> UK National Institute for Health and Care Excellence</a> (NICE)<br /><br /><b>Summary - Why Does the Evidence, or Lack Thereof, Remain Anechoic? </b><br /><br />Yet none of these reviews have gotten any significant attention in the US media or medical and health care literature, and the idea that Sovaldi has hardly been proven to be a miracle drug, or even better than older drugs for hepatitis C has not informed the US debate and the US outrage about its price.  Examples of the most recent outrage include <a href="http://www.forbes.com/sites/theapothecary/2014/06/17/the-sovaldi-tax-gilead-cant-justify-the-price-its-asking-americans-to-pay/">this in Forbes</a>,<br /> <br /><br /><blockquote class="tr_bq">A cure for hepatitis C is within reach for 170 million people around the world — thanks to the charitable efforts of poor and sick Americans who are picking up the tab by paying <i>outrageous prices</i> for their own treatment. It’s like Robin Hood in reverse. </blockquote><br />Also, <br /><br /><blockquote class="tr_bq"> It also took a complete lack of self-awareness — and <i>unmitigated gall</i> — to price Sovaldi the way Gilead has.</blockquote><br />Furthermore, Democrats in the US House of Representatives are calling for an investigation (which their Republican "colleagues" will doubtless block), <a href="http://www.bloomberg.com/news/2014-06-19/democrats-want-gilead-to-explain-84-000-cost-for-therapy.html">according to Bloomberg</a>,<br /><br /><blockquote class="tr_bq">The company 'did not provide a compelling justification for the high price they are charging for most patients,' Waxman and DeGette wrote  </blockquote><br /><br />If the price is outrageous for a miracle drug, it would be even more outrageous for a drug that has not been proven to be better than previously available treatments.<br /><br />The fact that skepticism about all the hype for Sovaldi has hardly touched the public discussion in the US is a prime example that the <a href="http://hcrenewal.blogspot.com/search/label/anechoic%20effect">anechoic effect</a> lives.  (The only skepticism from an expert could [probably only] be <a href="http://blogs.wsj.com/pharmalot/2014/06/12/will-oregon-restrict-coverage-for-a-pricey-gilead-pill-for-hepatitis-c/">found again in PharmaLot</a>, and came from one of the authors of the Center for Evidence Based Policy report [see above]). <br /><br /><blockquote class="tr_bq">'For most patients with hepatitis C, they have time to make those decisions,' Valerie King, one of the physicians at the center who worked on the Sovaldi review, tells OregonLive. 'I’m certainly not saying that this is a bad drug. I’m just saying that we don’t know that it is a good drug.' [<strong>UPDATE</strong>: King later called us to say that 'the research hasn't been extensive enough or transparent enough to tell us it is a good drug or bad drug, or has limited application.' This was based solely on assessing clinical research, not cost issue.]</blockquote><br />We have endlessly discussed the anechoic effect, that information and ideas that challenge the powers that be in health care, and particularly that challenge the ability of health care leaders and well-connected insiders to personally profit, often to a tremendous extent - the CEO of Gilead, John Martin, was <a href="http://www.fiercepharma.com/special-reports/biopharma-ceos-2013-john-martin-gilead">listed by FiercePharma </a>as the eighth highest paid biotech CEO in 2013, with total compensation of $15.45 million, before sales of Sovaldi really increased -  are considered recent unpleasantness that are just not to be discussed.  However, without open honest discussion of truths, however inconvenient or unpleasant, and the ideas that they suggest, health care will continue to degenerate into a plutocratically run, often corrupt swamp with ever increasing costs, and ever worsening access and quality, causing increasing suffering of patients and worsening of public health. <br /><br />A good place to start true health care reform might be honest discussion of the evidence about sofosbuvir.    <br /><br />

Fourth Time is the (Anti)Charm? - UK NICE Highlights "Uncertainties in the Evidence Base" About Sovaldi

As we have discussed, (here, here and here), while anger continues to build about the $1000/ pill price sought by Gilead for its new antiviral drug for hepatitis C, Sovaldi (sofosbuvir), almost all pu…

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The Smarming of Health Care - How to Spin a Minimally Efficacious Variant on an Old Drug as New and Wonderful

A recent announcement of the approval of a new drug showed the latest ways pharmaceutical companies can spin products as new and effective when in reality they are barely either.  <br /><br /><b>Announcing a Drug Approval with a Twist</b><br /><br />United Therapeutics just got US Food and Drug Administration (FDA) approval for their new oral prostacyclin agent for the treatment of pulmonary arterial hypertension. The basics, <a href="http://www.bloomberg.com/news/2013-12-21/united-therapeutics-wins-u-s-approval-for-lung-therapy.html">per Bloomberg</a>, were:<br /><br /><br /><blockquote class="tr_bq">United Therapeutics Corp. (UTHR)’s gained U.S. marketing approval for the oral version of its treatment for high blood pressure in the arteries that supply the lungs. <br /><br />The Food and Drug Administration cleared orenitram, an extended-release tablet, for the treatment of pulmonary arterial hypertension to improve exercise capacity in some types of patients, the Silver Spring, Maryland-based company said today in a statement. <br /><br />The pill’s active ingredient, treprostinil, is the same as in the company’s approved injection and inhalation solution for PAH, a life-threatening disorder, United Therapeutics said. The FDA had rejected the oral version of the therapy in March and in October> <br /><br />'This approval marks the first time that the FDA has approved an orally administered prostacyclin analogue for any disease -– and our fifth approval from the FDA for treatment of PAH -- supporting our mission of providing a wider choice of PAH therapies for physicians and patients,' Roger Jeffs, the company’s president and chief operating officer, said in the statement. 'We are grateful for the FDA’s thorough review and will continue to build clinical support for the use of Orenitram.' </blockquote><br /><br /><br />But the triumphant announcement by the company CEO had some unusual twists.  As<a href="http://www.npr.org/blogs/health/2013/12/24/256839330/orenitram-united-therapeutics-names-pill-after-ceo-who-sought-daughters-cure"> reported</a> on National Public Radio's (NPRs) Shots blog,<br /><br /><blockquote class="tr_bq">'When I started the company 17 years ago, the only option for treating pulmonary hypertension was intravenous ,' Martine Rothblatt, CEO of United Therapeutics told investors in a celebratory conference call Monday. '<i>My young daughter looked at me and said, 'Can't there be a pill?</i>''<br /><br />Now there is </blockquote><br />So,  <br /><br /><blockquote class="tr_bq">'What it has resulted in is<i> something that as the parent of a lovely young lady with pulmonary hypertension, I cannot even put into words, the emotional meaning that it has to have a pill form of prostacyclin,' Rothblatt said.</i></blockquote><br />It appears to be such a warm and happy story.  A mother is so concerned about her daughter's serious illness that she founds a company to develop treatments for it.  Now many years later they have come up with something groundbreaking.<br /><br />How could anyone not shed a tear?  How could anyone not be happy about this triumph of commercial drug development.<br /><br />However, while it may seem snarky to point this out, drug development is usually about issues other than "emotional meaning," and this discussion of emotional meaning took place during the public relations/ marketing blitz put on after the approval of the marketing of a new drug, so maybe closer examination, and some skepticism are warranted. <br /><br /><br /><b>How Well Does Orenitram Work?</b><br /><br />The quote above from the CEO was about "emotional meaning," not efficacy or effectiveness.  In fact, the blog post by Mr Hensley hinted at and a review of the one relevant published article strongly suggested that the drug really had minimal efficacy, and possibly benefits that failed to outweigh its harms.<br /><br />Mr Hensley wrote, <br /><br /><blockquote class="tr_bq"> The FDA approved Orenitram on the basis of a study that gauged its safety and effectiveness as a standalone treatment. The drug helped people <i>walk a little farther in a timed walking test. </i>The <i>most common side effects seen in the study were headache, nausea and diarrhea.</i></blockquote><br />On my review of the evidence....<br /><br />A single randomized controlled trial(1) showed that patients given treprostinil could walk on average 26 meters (less than 100 feet) more in 6 minutes after 12 weeks of treatment than they could at the beginning of the treatment, while those given placebo were only able to walk about as far as they did before.  The treated patients also had some improvement in their shortness of breath.  On the other hand, they were substantially more likely to experience adverse effects, particularly nausea, vomiting, diarrhea, flushing, jaw pain, or pain in the extremities.  <br /><br />Furthermore, the study lasted only 12 weeks, and provided no information about outcomes after that.  Treated patients were not spared overall worsening of their clinical situation compared to untreated patients.  Treated patients were no less likely to be hospitalized or to die.<br /><br />Various aspects of its design may increase doubts about its validity, including emphasis on a "modified intention-to-treat population" which was not clearly defined, a relatively high rate of premature study drug discontinuation, and a complex statistical analysis scheme which seemed unnecessary to assess the main results of a randomized controlled trial.<br /><br />Finally, the generalizability of the study was limited to patients already optimally treated with conventional therapy, and perhaps by ist predominantly Asian female population. <br /><br />So the only apparently positive trial of trepronsinil did not provide good evidence that its benefits outweighed its harms.  At best, some patients might find that the modest increases in exercise capacity and decreases in dyspnea it may produce may be worth nausea, vomiting, diarrhea, flushing, or jaw or extremity pain.   <br /><br />Note that treprostinil is an oral version of a type of compound called a prostacyclin.  As noted above, United Therapeutics markets other forms of prostacyclin.  However, the latest (2005) Cochrane Collaboration systematic review of this class of drugs for pulmonary arterial hypertension only found evidence that the drugs helped when added to first-line drugs to improve symptoms for the short-term, no more than 12 weeks.  It found no evidence that prostacyclin prolongs survival, or lessens complications of the illness(2)  <br /><br />So having an oral prostacyclin treatment for PAH may have emotional meaning, but the pill, while likely more convenient than an injectable prostacyclin, does not seem to have sufficient efficacy to outweigh its harms for many patients.  <br /><br /><b>What Does Orenitram Cost, and Why?</b><br /><br />But United Therapeutics may have been able to make one aspect of this drug superlative, - its price.  Per Scott Hensley in the Shots blog,<br /><br /><blockquote class="tr_bq">Orenitram won't be available for sale for about six months, the company said, and its exact price hasn't been determined either. But<i> it will be very expensive, about<b> $150,000 a year</b>, </i>according to an estimate by Dr. Mark Schoenebaum, an industry analyst with ISI.</blockquote><br />That would be about three times the median US family income.  But the CEO shrugged concerns about the price off,<br /><br /><blockquote class="tr_bq">Rothblatt acknowledged that the cost of the drugs is high but manageable, because pulmonary hypertension remains pretty rare, though the exact prevalence is hard to pin down.</blockquote><br />One explanation for that amazingly high price comes from a <a href="http://www.forbes.com/sites/matthewherper/2013/12/23/this-drug-company-ceo-just-named-her-new-drug-after-herself/">post</a> on Forbes by Matthew Herper,<br /><br /><blockquote class="tr_bq">She commercialized [prostacyclin] ..., and was able to get investors interested because she realized there was<i> no maximum price </i>insurers would pay for an effective drug. United Therapeutics became one of biotech’s great success stories.</blockquote><br />A lack of an upper limit on pricing has other effects of course.  <a href="http://financials.morningstar.com/ratios/r.html?t=UTHR&region=usa&culture=en-US&ownerCountry=USA">According to Morningstar</a>, the company's sky high pricing enabled a net profit margin over 33% in 2012-13.   According to the <a href="http://ir.unither.com/common/download/download.cfm?companyid=UTHR&fileid=660323&filekey=f90b5dc7-52ac-4a2a-9350-8446eaeee34d&filename=UTHR_2013_Proxy_Statement_v2.pdf">United Therapeutics 2013 proxy statement</a>, CEO Martine Rothblatt's total compensation is<b><i> $7,958,328</i></b>.  Three other executives got more than $4.5 million.<br /><br />So I imagine that marketing a drug that may produce so much revenue may have emotional meaning for company executives.  On the other hand, in this era of high insurance deductibles and co-payments it may have considerable negative emotional meaning for patients. <br /><br /><b>Some Off-Key Notes</b><br /><br /><br />The recent publicity about the new oral prostacyclin did not dwell on an issue that appeared earlier in a December, 2013, <a href="http://ir.unither.com/releasedetail.cfm?ReleaseID=812424">press release</a> from United Therapeutics about its other prostacyclin products,<br /><br /><blockquote class="tr_bq"> United Therapeutics Corporation (NASDAQ: UTHR) announced today that it has received a subpoena from the Office of the Inspector General of the Department of Health and Human Services reflecting <i>an investigation by the United States Department of Justice</i>, principally represented by the United States Attorney's Office in Baltimore. The subpoena requests <i>documents regarding Remodulin® (treprostinil) Injection, Tyvaso® (treprostinil) Inhalation Solution and Adcirca® (tadalafil) Tablets, including the company's marketing practices relating to these products.</i></blockquote>Instead, as we discussed above, the CEO of the company that will market this very expensive but not very efficacious drug went out of her way to bring up emotional issues about her own daughter's illness.  Certainly, anyone can believe the CEO was motivated to develop prostacyclins for PAH by concerns about her daughter's own illness.  However, focusing on such emotional issues may also distract from concerns about other aspects of the company's marketing. <br /><br />So maybe it is not a surprise that she decided to name the new drug in a personal way,...  But she did not name it for her daughter.  Again per Scott Hensley,<br /><br /><blockquote class="tr_bq"> Now there is: Orenitram. The<i> name comes from 'Martine Ro,' as in Martine Rothblatt, backward.</i></blockquote><br />Instead, Martine Rothblatt names her company's new drug for.... herself. <br /><br />So what is this very emotional and personal drug marketing/ public relations campaign really about? <br /><br /><br /><b>On Smarm in Health Care </b><br /><br />So it appears that United Therapeutics and its CEO used what may now be called smarm to promote their vested interests and divert attention from uncomfortable facts. <br /><br />In a now widely read and commented upon article in Gawker, Tom Scocca asserted that smarm has become "an omnipresent, unnamed cultural force."  Some aspects of smarm, as discussed in the article,<br /><br /><blockquote class="tr_bq">Smarm is a kind of performance—an assumption of the forms of seriousness, of virtue, of constructiveness, without the substance.</blockquote><br /><blockquote class="tr_bq"> it expresses one agenda, while actually pursuing a different one. It is a kind of moral and ethical misdirection. Its genuine purposes lie beneath the greased-over surface.</blockquote><br /><blockquote class="tr_bq"> Smarm, whether political or literary, insists that the audience accept the priors it has been given. Debate begins where the important parts of the debate have ended.</blockquote><br />So the smarmy element in the public relations about Orenitram was the misdirection created by invoking the CEO's daughter's illness and its emotional ramifications.  By focusing on an emotional issue which apparently only the callous could dismiss, the issues of the drug's minimal efficacy, frequent side effects and very high price were eclipsed.   Yet they, not the emotional connection between a particular parent and chile should be salient to patients, doctors, regulators, and the general public.<br /><br /> (The issues of the investigation of the company's marketing of other prostacyclin products, and the egotism implied by the drug's name were certainly eclipsed as well.) <br /><br />Presumably by raising these truths which might be unpleasant to United Therapeutics executives, I am now guilty of "snark."  As Scocca pointed out, one aspect of smarm is to exile reasonable criticism and skepticism as "snark,"<br /><br /><blockquote class="tr_bq">What is snark reacting to? <br /><div data-textannotation-id="723f1b5670939f8ac0e1ede8374c51aa"><br /></div><div data-textannotation-id="723f1b5670939f8ac0e1ede8374c51aa">It is reacting to smarm. </div></blockquote><div data-textannotation-id="723f1b5670939f8ac0e1ede8374c51aa"><br /></div><div data-textannotation-id="723f1b5670939f8ac0e1ede8374c51aa">So snarky as it may be, I believe that the major considerations for patients and physicians when considering a therapy - like Orenitram - should be the benefits versus harms of the the therapy for the individual patient, and the strength of the evidence supporting both.  The more marketers, public relations functionaries, and executive try to distract from that, and the more smarm they employ to do so, the more skepticism is required.  </div><br /><br /><b>References</b><br /><br />1.  Jing ZC, Parikh K, Pulido T et al.Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial.  Circulation 2013; 127: 624-633. Link <a href="http://circ.ahajournals.org/content/127/5/624.full">here</a>.<br /><br />2. Paramothayan NS, Lasserson TJ, Wells A et al.   Prostacyclin for pulmonary hypertension in adults. Cochrane Review 2005; Link <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD002994.pub2/abstract;jsessionid=631C530B905482CD4A1108101CF1D775.f04t04">here</a>.

The Smarming of Health Care - How to Spin a Minimally Efficacious Variant on an Old Drug as New and Wonderful

A recent announcement of the approval of a new drug showed the latest ways pharmaceutical companies can spin products as new and effective when in reality they are barely either.  Announcing a Drug Ap…

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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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"The Scent ... of a Casino" - Clinical Research Results as Fodder for Insider Trading

<i>"The scent and smoke and sweat of a casino are nauseating at three in the morning. Then the soul-erosion produced by high gambling - a compost of greed and fear and nervous tension - becomes unbearable and the senses awake and revolt from it."</i> - Ian Fleming.  Casino Royale.  1953<br /><br />A major theme of this blog has been threats to the integrity of clinical research.  When I started out as a young naive academician in medicine, I viewed clinical research through the lens of <a href="http://hcrenewal.blogspot.com/search/label/evidence-based%20medicine">evidence-based medicine</a>, as primarily a means to develop better evidence to aid in the care of patients, and secondarily a way to advance science and public health.  Yet in the past 20 to 30 years, clinical research has become commercialized.  Now most randomized controlled clinical trials are done to support the licensing of drugs and devices for particular indications.  Furthermore, clinical research has become de facto a primary avenue of marketing of drugs and devices.  So we have discussed endlessly how clinical research has been <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulated</a> by those with vested interests in selling drugs and devices, and may be <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppressed</a> when even such manipulation fails to produce results desired by commercial sponsors.<br /><br />If that was not bad enough - and it is - now there is evidence that clinical research has become the roulette wheel in an investment casino.  This is the lesson provided by new US government charges that giant hedge fund SAC Capital used insider knowledge to trade drug company stocks.<br /><br /><br />Let me try to provide a narrative of the key elements of the case.<br /><br /><b>The Key Players</b> <br /><br /><i>Matthew Martoma</i> was a " former student at Harvard Law School, ... [who] co-wrote papers on medical ethics before seeking a business degree at Stanford University and joining a little-known Boston hedge fund."  Then, "in 2006, at age 32, Martoma made it to <i>SAC Capital Advisors</i> LP and gained the attention of the firm’s billionaire owner <i>Steven A. Cohen</i>."(1)<br /><br /><i>Dr Sidney Gilman</i> is<br /><br /><blockquote class="tr_bq">an 80-year-old neurologist with expertise in neurodegenerative disorders, including Alzheimer’s disease. According to his <a href="http://www.med.umich.edu/neurology/faculty/gilman_research_bio.htm">biography</a> on the University of Michigan website, Gilman first served on the faculty at Harvard and Columbia and then had a long and distinguished career at the University of Michigan, where he was the chair of the department of neurology for many years. He is a member of the Institute of Medicine of the National Academy of Sciences and a past president of the American Neurological Association. In other words, he’s a bigshot.<br /><br />Gilman moonlighted as a consultant, working for an expert networking firm, where he provided advice to the financial industry (and which eventually led to the insider trading case), and for Elan Pharmaceuticals. In addition to his consulting for Elan, he also served as the <i>chair of the Safety Monitoring Committee for a phase II clinical trial of a highly promising (at the time) Alzheimer’s drug, bapineuzumab, under development by Elan and Wyeth</i>.(2)</blockquote><br />The owner of SAC Capital, a hedge fund worth $14 billion, is <i>Steven A Cohen</i>, "a prodigious art collector, an investor in the New York Mets, a supporter of Mitt Romney’s presidential campaign."  His "career ... has reached mythic status on Wall Street. Over the last 20 years, Mr. Cohen has amassed a multibillion-dollar fortune by posting returns averaging 30 percent a year. SAC has grown into a firm with about 1,000 employees around the world."(3)<br /><br /><b>The Maneuver</b><br /><br /><br />Per the NY Times(4),  <br /><br /><blockquote class="tr_bq">The doctor met Martoma as a consultant for an expert- networking firm based in Manhattan and had sessions with Martoma from mid-2006 to July 2008, according to the government. <br /><br />Gilman worked for Gerson Lehrman Group’s Scientific Advisory Board starting in 2002,...  </blockquote><br />Also according to the NY Times(5)<br />  <br /><blockquote class="tr_bq"><i>Dr. Gilman’s consulting work for Mr. Martoma earned him about $108,000</i>, according to court filings. Based in part on <i>Dr. Gilman’s leaks about positive developments related to the clinical trials of a new Alzheimer’s drug, SAC accumulated a roughly $700 million position in the stocks of Wyeth and Elan,</i> according to the government.<br /><br />The S.E.C. said that <i>the fund’s owner, Mr. Cohen, took a large position in Wyeth and Elan in his personal portfolio based on Mr. Martoma’s recommendation</i>. Mr. Cohen maintained his holdings even though there was significant internal debate about the wisdom of such a large position in the drug makers, the government said.</blockquote>Furthermore, per Larry Husten writing in Cardiobrief(2),<br /><br /><blockquote class="tr_bq"> While serving on the Safety Monitoring Committee of the trial, from the summer of 2006 through mid-July 2008, <i>Gilman had access to the safety (but not the efficacy) data from the trial. Throughout this period he leaked the positive safety information to his contact at SAC</i> (the enormous hedge fund), which then began to accumulate a large position in both Elan and Wyeth.</blockquote><br /><br />So, allegedly based on information from Dr Gilman, the high-ranking academic physician doubling as a data monitoring committee chair for a drug trial, paid for these services by Elan, SAC Capital and Mr Cohen made a large investment in Elan and Wyeth, the companies sponsoring the trial.<br /><br />But then, again per Husten(2),<br /><br /><blockquote class="tr_bq"> Later in June, Elan chose Gilman to present the full trial data at ICAD. Gilman did not become privy to this data until the middle of July when Elan gave him the full results of the trial. <i>The results, in sharp contrast to the earlier view in the press release, were decidedly negative, </i>offering little hope that the drug would be considered effective. Gilman apparently understood this, because <i>he immediately gave the results to the hedge fund, which then rapidly and dramatically reversed its long position on Wyeth and Elan.</i></blockquote><br />Specifically, per the New York Times(5), after<br /><br /><blockquote class="tr_bq"><i>Dr. Gilman told Mr. Martoma that patients were experiencing serious side effects</i>, prosecutors say. Afterward, <i>Mr. Martoma e-mailed Mr. Cohen</i>, telling him 'it’s important' that they speak. They spoke on the phone for nearly 20 minutes, the government says, and <i>Mr. Martoma told his boss that he was no longer 'comfortable' with the investments.</i><br /><br />The following day, SAC reversed course. <i>Mr. Cohen’s head trader sold the firm’s entire inventory of roughly 10.5 million shares of Elan and about seven million shares of Wyeth</i>, the government said. Once it had dumped the shares, <i>SAC built a short position in the two stocks, betting their value would drop.</i><br /><br />According to the S.E.C., the trader, Mr. Cohen and Mr. Martoma <i>kept the sales confidential.</i> The trade, wrote the head trader in an e-mail to Mr. Cohen, 'was executed quietly and efficiently over a four-day period through algos and darkpools' — referring to trades using algorithms and to trading platforms that do not have the same reporting requirements as the stock exchanges — 'and booked into two firm accounts that have very limited viewing access.'<br /><br />After the companies announced the results of the trials, Elan’s stock fell about 42 percent and Wyeth’s about 12 percent.<br /><br /><i>The trading allowed SAC to avoid about $194 million in losses and earn about $83 million in profits </i>on Elan and Wyeth, according to prosecutors.<br /><br />At the end of 2008, <i>Mr. Martoma received a bonus of about $9.3 million</i>, the S.E.C. said. </blockquote><br />So, having bet heavily on Elan and Wyeth based on Dr Gilman's initial information that the trial was showing positive results, SAC Capital and Mr Cohen then bet heavily against these companies based on Dr Gilman's new information that the trial would end up not showing such results.  Because they had this information allegedly before it was made public, these bets yielded huge profits.  Mr Martoma, the conduit between SAC Capital and allegedly Mr Cohen, made millions.  Dr Gilman made over a hundred thousand. <br /><br /><b>The Charges</b><br /><br />Per Bloomberg(4),<br /><br /><blockquote class="tr_bq">Martoma, 38, was accused by prosecutors in Manhattan federal court with <i>playing a lead role in what they called the most lucrative insider-trading scheme in history,</i> given the $276 million profit he allegedly helped the hedge fund achieve.</blockquote>The government started off taking a tough approach, per the NY Times(5),<br /><br /><blockquote class="tr_bq"><i>FBI agents arrested Mr. Martoma</i>, 38, early Tuesday morning at his home in Boca Raton, Fla. He was released on bail after making an appearance in Federal District Court in West Palm Beach. Mr. Martoma, who has been unemployed since leaving SAC in 2010, is expected to appear in federal court in Manhattan on Monday and enter a plea.</blockquote><br /> In addition, Dr Gilman, per Bloomberg(1), "has <i>entered into a non- prosecution agreement </i>with prosecutors in which he agreed to testify before a federal grand jury and to <i>forfeit $186,761, money which he was paid by Elan for his consulting work."</i><br /><br />Mr Cohen has not been charged.  However, according to John Cassidy writing in the New Yorker(6),<br /><br /><blockquote class="tr_bq">the complaints do <i>assert that Cohen, identified as 'Portfolio Manager A,' personally authorized many of Martoma's trades, and pocketed the bulk of the profits they generated</i>.  In a statement accompanying the indictment [US Attorney Preet] Bharara was careful to state that S.AC., and by extension Cohen, <i>reaped enormous rewards from the criminal wrongdoing,</i> even though they weren't being charged.</blockquote><div style="background-color: white; border: medium none; color: black; left: -1001px; overflow: hidden; position: absolute; text-align: left; text-decoration: none; top: -1000px;">the complaints do assert that Cohen, identified as “Portfolio Manager A,” personally authorized many of Martoma’s trades, and pocketed the bulk of the profits they generated. In a statement accompanying the indictment, Bharara was careful to state that S.A.C., and by extension Cohen, reaped enormous rewards from the criminal wrongdoing, even though they weren’t being charged. <br /><br />Read more: <a href="http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdLAchwv" style="color: #003399;">http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdLAchwv</a></div><div style="background-color: white; border: medium none; color: black; left: -1001px; overflow: hidden; position: absolute; text-align: left; text-decoration: none; top: -1000px;"><br /><br />Read more: <a href="http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdKdZcAY" style="color: #003399;">http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdKdZcAY</a></div>In addition, there is now some likelihood that there will be legal actions against SAC Capital.  The company has reportedly received a "Wells notice" that the SEC is considering pursuing such action.  In addition, according to the New York Times(7), "an additional action against SAC, or even Mr. Cohen, could involve accusations of fraud based on the so-called control-person liability theory, meaning that it was in 'control' of Mr. Martoma when he engaged in insider trading."<br /><div style="background-color: white; border: medium none; color: black; left: -1001px; overflow: hidden; position: absolute; text-align: left; text-decoration: none; top: -1000px;">the complaints do assert that Cohen, identified as “Portfolio Manager A,” personally authorized many of Martoma’s trades, and pocketed the bulk of the profits they generated. In a statement accompanying the indictment, Bharara was careful to state that S.A.C., and by extension Cohen, reaped enormous rewards from the criminal wrongdoing, even though they weren’t being charged.<br /><br />Read more: <a href="http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdKdZcAY" style="color: #003399;">http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdKdZcAY</a></div><br /><br /><b>Summary</b><br /><br />At one point, I would have simply regarded the trial of bapineuzumab as a clinical scientific experiment meant to determine if a promising new therapy would work for the important clinical problem of Alzheimer's disease, and incidentally as means to learn more about the biology of that disease.  More recently, I would have regarded the trial as primarily a means for Elan and Wyeth to persuade the US Food and Drug Administration to approve this drug as a treatment for this disease, and then if so, a means for these companies to market it.  I would have been skeptical about the value of the clinical evidence supplied by the trial to support use of this drug, but would not have dismissed this evidence out of hand.<br /><br />Now it appears that a major role of this trial was to be a roulette wheel in a Wall Street casino.  Big bettors on this wheel included people who may have had advance knowledge about the slot in which the ball would land.<br /><br />Ideally, clinical research ought to be done by people who have no particular interest in the results turning out one way or the other.  Obviously, clinical investigators as humans may have opinions about how studies might turn out.  However, they should not be in positions to gain or lose money according to the results, or to be intimidated by those with interests in having the studies obtain particular results. Our current system in which many clinical studies are funded by organizations with interests in how the results turn out has lead to numerous cases of <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation</a> of study results, and sometimes <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppression</a> of studies whose results could not be manipulated successfully in the desired direction.  Such threats to study integrity make it difficult to make the best clinical decisions for individual patients, distort health policy, and break the trust of patients who volunteered to participate in the studies.<br /><br />Now it appears that short-term stock trading that bets on the results of clinical research, sometimes informed by insider information about these results, could be another powerful external influence on clinical research that could additionally threaten its integrity.  Furthermore, as we speculated seven years ago (see <a href="http://hcrenewal.blogspot.com/2005/09/wall-street-and-clinical-trials.html">this post </a>and links backward), fear of insider trading may be making clinical research more opaque, and this opacity may allow even more control of research by sponsors (companies funding it) rather than investigators.<br /><br />We have previously suggested that real consideration ought to be given to taking clinical research out of the hands of organizations, particularly health care corporations, that have vested interests in the direction of the results.  Knowledge that clinical research is increasingly becoming a casino for stock traders and hedge funds, and that research results are becoming the stuff of insider trading should further prompt this consideration.  <br /><br /><br /><span style="font-size: x-small;"><b>References</b></span><br /><span style="font-size: x-small;">1.  Burton K, Kishan S, Van Voris B. Cohen's 'Elan Guy' Martoma dropped ethics for hedge fund.  Bloomberg, Nov 23, 2012.  Link <a href="http://www.businessweek.com/news/2012-11-23/cohen-s-elan-guy-martoma-dropped-ethics-for-hedge-fund">here</a>.   </span><br /><span style="font-size: x-small;">2.  Husten L. The doctor and the center of the insider trading scandal.  Cardiobrief, Nov 27, 2012.  Link <a href="http://cardiobrief.org/2012/11/27/the-doctor-at-the-center-of-the-insider-trading-scandal/">here</a>.</span><br /><span style="font-size: x-small;">3.  Lattman P. S.E.C. weighs suit against SAC Capital.  New York Times, Nov 28, 2012.  Link <a href="http://dealbook.nytimes.com/2012/11/28/securities-and-exchange-commission-weighs-suing-sac-capital/">here</a>. </span><br /><span style="font-size: x-small;">4.  Van Voris B, Hurtado P. Insider crackdown uses SAC manager in health-care pivot.  Bloomberg, Nov 21, 2012.  Link <a href="http://www.bloomberg.com/news/2012-11-21/insider-crackdown-uses-sac-manager-in-healthcare-pivot.html">here</a>. </span><br /><span style="font-size: x-small;">5.  Lattman P. Insider inquiry inching closer to a billionaire.  New York Times, Nov 20, 2012.  Link <a href="http://dealbook.nytimes.com/2012/11/20/federal-prosecutors-charge-former-sac-capital-trader/">here</a>.</span><br /><span style="font-size: x-small;">6.  Cassidy J. It's time for Obama to bite the hedge-fund sharks.  New Yorker, Nov 21, 2012.  Link <a href="http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html">here</a>.</span><br /><span style="font-size: x-small;">7.  Lattman P. S.E.C. weighs suit against SAC Capital.  New York Times, Nov 28, 2012.  Link <a href="http://dealbook.nytimes.com/2012/11/28/securities-and-exchange-commission-weighs-suing-sac-capital/">here</a>.  </span>

"The Scent ... of a Casino" - Clinical Research Results as Fodder for Insider Trading

"The scent and smoke and sweat of a casino are nauseating at three in the morning. Then the soul-erosion produced by high gambling - a compost of greed and fear and nervous tension - becomes unbearabl…

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When Clinical Trials are Meant for Marketing, not Science

The development of the randomized controlled clinical trial (RCT) was one of the major scientific advances in clinical medicine.  RCTs provide a major part of the evidence underlying evidence based medicine.  RCTs provide a major source of data used by the US Food and Drug Administration, and similar agencies in other countries, to decide whether to approve drugs or devices to manage particular clinical problems.  Unfortunately, with the rise of the RCT came a rise in attempts to <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppress</a> and <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulate</a> clinical trials by those with vested interests, often in selling the products and services the trials can evaluate.<br /><br />Many of the examples we have discussed were of attempts at manipulation or suppression of clinical trials originally done to provide evidence for product approval, or even ostensibly to advance clinical science.  Yet a relatively new article covering evidence revealed from litigation about the drug gabapentin (Neurontin) originally made by Parke-Davis, first a part of Warner Lambert, now part of Pfizer suggests that many clinical trials may not be done to advance science, or even just to provide data to regulators, but only to market products.<br /><br />The article is Vedula SS, Goldman PS, Rona IJ, Greene TM, and Dickersin K. Implementation of a publication strategy in the context of reporting biases: a case study based on new documents from the Neurontin litigation.  Trials 2012; 13: 136.  Link<a href="http://www.trialsjournal.com/content/13/1/136"> here</a>.<br /><br /><b>Methods Summary</b><br /><br />The article described a case study based on documents revealed in 2008 litigation.  The purpose of the study was:<br /><br /><blockquote class="tr_bq">to describe the implementation of a publication strategy for off-label marketing of gabapentin, within the context of reporting biases and spin of Pfizer and Parke-Davis’s clinical trial findings, for four off-label uses: migraine prophylaxis, treatment of bipolar disorders, neuropathic pain, and nociceptive pain. </blockquote><br />The study examined documents revealed through the 2008 litigation.  It concentrated on documents relating to the marketing of Neurontin for four off-label indications, that is, for four potential reasons to use the drug which had not yet been approved by the US FDA.  It focused on documents discussing strategies for marketing for these indications, and then documents about particular company sponsored RCTs done for these indications. <br /><br /><b>Strategies to Sell Drugs</b><br /><br />The documents examined by the investigators showed that Parke-Davis prepared "marketing assessments" for four possible indications for Neurontin.  The assessments discussed two possible strategies.  The "indication strategy" would be to conduct trials for the purposes of providing data to the FDA in the hope that the FDA would then approve the new indication for the drug.  The "marketing strategy" would be, in the words of an internal company memo quoted in the study, to conduct clinical trials and<br /><br /><blockquote class="tr_bq">to disseminate the information as widely as possible through the world’s medical literature</blockquote><br />In other words, the publication strategy involved using RCTs first for marketing, rather than scientific or regulatory purposes. <br /><br /><b>How the Trials were Controlled by Marketers  </b><br /><br />The publication strategy involved not simply doing trials and publicizing their results, but controlling the messages conveyed by the trials to make sure they primarily supported marketing.  This was done by having the company's marketing department control the content of the trial reports.<br /><br /><blockquote class="tr_bq"><i> A Neurontin Publications Subcommittee (NTN PSC) was formed within Pfizer and Parke-Davis to implement a publication plan.</i> Minutes from meetings between the NTN PSC and Medical Action Communications (MAC), a medical writing company, indicate that <i>a list of key messages, guiding the content of published reports related to the trials of gabapentin for off-label indications, was developed based on a branding guide </i></blockquote>Thus it appeared to be that marketers, not physicians or scientists were in control of supposedly scholarly research publications appearing in medical journals. <br /><br />The marketers controlled content by controlling those who wrote it.<br /><br /><blockquote class="tr_bq"> A standard operating procedure related to publication of affiliate-driven manuscripts was identified in internal company documents dated October 16, 2002, and it sheds further light on the publication planning process (see Figure 3<a href="http://www.trialsjournal.com/content/13/1/136/figure/F3"></a>). (The term affiliate in this context refers to Pfizer’s foreign affiliates, that is, corporations related to Pfizer by either shareholdings or other means of control, including subsidiary, parent, or sibling corporations). According to the internal company documents, 'affiliate-driven <i>manuscripts' were written for Pfizer and Parke-Davis by MAC</i> and sent to the authors for approval. <i>Each article was coordinated by a manuscript team, consisting of representatives from the medical and marketing divisions of the company.</i> The documents also indicate that all <i>affiliate-driven manuscripts should be forwarded to the NTN PSC for review. One of the objectives of manuscripts being reviewed by the NTN PSC was to ‘ensure that they are in-line with current product messages and areas of interest’</i></blockquote><b>Manipulating the Dissemination (and Analysis) of Research Results </b><br /><br />Note that the control of publication by marketers describe above involved ghost-writing of articles by medical education and communications companies (MECCs).  Later the article explained that these ghost writers were "not appropriately acknowledged" in the resulting published articles.<br /><br />The Vedula et al study article provided examples of "spin" in the writing of again supposedly scholarly research publications used in fact to support marketing, and controlled if not composed by marketers.<br /><br /><blockquote class="tr_bq"> We identified spin in publications related to 8/12 trials included in our analysis.... We classified the following as spin: <i>emphasis in the published report on outcomes that were not specified in the study protocol</i> (Study 879–201) ...; conclusions that did not match study findings described in the internal company research report (Study 945–220) <a href="http://www.blogger.com/blogger.g?blogID=9551150" name="d7865e503"></a>...; extensive rationale to explain away statistically non-significant (unfavorable to the sponsor) findings (Study 945–209; 945–291; No study number - Gorson) <a href="http://www.blogger.com/blogger.g?blogID=9551150" name="d7865e508"></a><a href="http://www.blogger.com/blogger.g?blogID=9551150" name="d7865e510"></a><a href="http://www.blogger.com/blogger.g?blogID=9551150" name="d7865e512"></a>...; conclusion of treatment effectiveness from an uncontrolled study (Study 945–250) ...; emphasis on statistically significant secondary outcomes despite negative findings for the primary outcome (Study 945–271) ...; and an explicit description of an attempt to spin study findings (as described in internal company emails) (Study 945–306).</blockquote><br />Note that while most of these examples of spin involved manipulation of the dissemination of study results, that is, doubtful, biased or fallacious arguments based on apparently unbiased data, they also involved manipulation of the analyses (in italics). <br /><br />The article also described manipulation of dissemination involving the timing of publication, including delaying publication of an article despite the wishes of the study's investigators because the results were not statistically significant, and hence not favorable for marketing.  <br /><br /><b>Summary</b><br /><br />Documents revealed by litigation about Neurontin in 2004 provided insights about how pharmaceutical and presumably other kinds of health care corporations may conduct systematic, deceptive stealth marketing campaigns to promote their products and services (look<a href="http://hcrenewal.blogspot.com/2006/08/stealth-marketing-of-neurontin.html"> here</a>).  We noted that initial media coverage of documents revealed in the 2008 litigation also suggested the existence of a systematic "publication strategy" to control dissemination of results of particular trials, while suppressing trials whose results could not easily be spun to provide support of marketing objectives (look <a href="http://hcrenewal.blogspot.com/2008/10/did-pfizer-marketers-suppress-and.html">here</a>).<br /><br />Now the new paper by Verdula et al fill out our knowledge of this case.  The paper suggests that randomized controlled clinical trials may be done not to advance science, or even convince regulators, but primarily to market their sponsors' products.  Thus some significant proportion of the clinical research literature, the literature that physicians and other health professionals have relied upon to make evidence-based decisions for their patients, may exist mainly for marketing purposes.  Even the most rigorous methods used by clinical epidemiologists to review research are meant to discover problems that arose from human error or the inevitable trade-offs made when research is done in the real world, but not deliberately introduced biases and defects meant to promote vested interests.  Thus it is not clear that even the most "evidence-based" medical decisions are based on real scientific evidence rather than the spinning of marketers.<br /><br />Thus health care professionals, policy makers, researchers, and the interested public need to be even more skeptical about arguments made to promote innovative treatments and other clinical interventions.  However, it is not clear that even rigorous skepticism can defend the integrity of evidence based medicine from marketing disguised as clinical research. <br /><br />Going forward, we must consider erecting an impregnable barrier between clinical research and those whose primary interest is to make money by selling health care goods and services.  If we do not do that, we will forever need to worry that we really have no idea what "works in medicine," and whether any particular test, treatment, or program provides benefits that outweigh its harms.  <br /><br />

When Clinical Trials are Meant for Marketing, not Science

The development of the randomized controlled clinical trial (RCT) was one of the major scientific advances in clinical medicine.  RCTs provide a major part of the evidence underlying evidence based me…

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"MetroHealth, Explorys use huge patient database to revolutionize medical research"

As I have written in the past, beware claims of "revolutions" where healthcare or medical research are involved.  As in a slide in my recent <a href="http://hcrenewal.blogspot.com/2012/08/my-presentation-to-health-informatics.html" target="_blank">presentation</a> to the Health Informatics Society of Australia on healthcare IT trust, I asked:<br /><br /><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZx4YeKPPlUpYdQHrz-L-Iu_RzvWcGlVYGDmgAVoiQq9tfEitVSmBehI6oQQIvzhqWY-qLj_kqUYEZUvzoy-V2DbPQdsAbN0OyQ-4ohoRVIzRPX1iXmJLhLMxk_QQCo5NeMxZnyrpn1nbJ/s1600/slide1.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZx4YeKPPlUpYdQHrz-L-Iu_RzvWcGlVYGDmgAVoiQq9tfEitVSmBehI6oQQIvzhqWY-qLj_kqUYEZUvzoy-V2DbPQdsAbN0OyQ-4ohoRVIzRPX1iXmJLhLMxk_QQCo5NeMxZnyrpn1nbJ/s320/slide1.jpg" width="320" /></a></div><br /><br />In that same talk, I pointed out the "revolutions" usually have downsides, and IT always produces winners and losers (per the empirical research of <a href="http://rkcsi.indiana.edu/" target="_blank">Social Informatics</a>).  <br /><br />I also asked "<i>have we suffered a complete breakdown in the scientific method with regard to EHR and clinical IT?</i>" in a 2009 post on uncontrolled EHR data and comparative effectiveness studies <a href="http://hcrenewal.blogspot.com/2009/04/have-we-suffered-complete-breakdown-in.html" target="_blank">at this link</a>.   <br /><br />In the Aug. 29, 2012 article "<a href="http://www.cleveland.com/healthfit/index.ssf/2012/08/metrohealth_and_explorys_are_u.html" target="_blank">MetroHealth, Explorys use huge patient database <b>to revolutionize </b>medical research</a>"  in The Plain Dealer (Ohio), the following claims are proffered.  I am assuming regarding this article, as in newspaper articles I make contributions to, that the researchers were involved in its provenance and content:<br /><br /><blockquote class="tr_bq">Large databases of electronic medical records hold great promise for medical research. In theory they can provide doctors access to huge amounts of anonymous patient data, allowing large-scale population studies without the cost and hassle of patient recruitment, review boards and staff training.<br /><br />Now, a team of data experts at MetroHealth Medical Center and the Cleveland Clinic Innovations spinoff company <a href="https://www.explorys.com/about-us">Explorys</a> has shown just how powerful such medical records can be: In three months, they've replicated a major medical study that took a Norwegian team 14 years to research and report. And they've done it at a fraction of the cost, with a sample about 40 times as large.<br /><br />The local effort, led by MetroHealth Chief Medical Informatics Officer <a href="http://www.metrohealth.org/physiciandirectory/PhysicianDetail.aspx?ID=029298">Dr. David Kaelber</a>, was possible because of Explorys' database of 14 million electronic medical records gathered from 12 major health systems. </blockquote><br />14 million records gathered from 12 major health systems, which may in fact be using disparate EHR systems or versions, is almost indisputably <b>not</b> controlled data.<br /><br />A comparison to a more rigorous study was conceptualized and performed:<br /><br /><blockquote class="tr_bq">Most of all though, he [Kaelber] needed to prove that it worked -- that he could get exactly the same results as traditional research studies that required more time and resources.<br /><br />Enter the <a href="http://atvb.ahajournals.org/content/31/6/1439.abstract?sid=9212fce2-301c-4e47-9c70-545442fdc21e">Norwegian study</a>. In 1994, a group of researchers started registering 26,714 people in the northern region's largest city, Tromso. It was part of a much longer study on the population's heart disease risk. They recorded height, weight and other measures of obesity, then followed participants for 13 years, recording any blood clots they had.<br /><br />Their conclusion: the combination of obesity and a tall stature significantly increases risk of blood clots, especially in men. </blockquote><br />The same hypothesis was tested with the uncontrolled EHR data, with claims that (obviously) the time and expense were lower, at least in the instant sense (costs of EHR implementation and maintenance in 12 major health systems could be in the billions of dollars at a time when a health system can easily spend $100 million each over just a few years as Bob Wachter points our <a href="http://community.the-hospitalist.org/2012/09/03/putting-the-a-back-in-soap-notes-time-to-tackle-an-epic-problem/" target="_blank">here</a> - one hundred million dollars for UCSF):<br /><br /><blockquote class="tr_bq">... The sample: 959,030 patients with medical records in the Explorys platform. The method: using software to search for blood clots in the health and claims records contained in the database, and then looking for patterns in those patients' height and weight. The result: Exactly the same as the Tromso study.<br /><br />"And actually the statistical significance of our study was much, much higher because our sample size was 40 times greater," Kaelber said. Kaelber and his team published their results online in July in the <a href="http://jamia.bmj.com/" target="_blank">Journal of the American Medical Informatics Association</a>.</blockquote><br />The conclusion to the article <a href="http://jamia.bmj.com/content/early/2012/07/01/amiajnl-2011-000782.abstract" target="_blank">here</a> (<b>subscription required</b>) was:<br /><br /><blockquote class="tr_bq">With the right clinical research informatics tools and EHR data, some types of very large cohort studies can be completed <i style="color: #e06666;"><b>[and, by implication, trusted and acted upon at local, regional or societal levels - ed.]</b></i> with minimal resources. </blockquote><br /><span class="commentBody" data-jsid="text">This data was, and I don't think this can be refuted, poorly controlled.  There are limits to what "data cleansing" and standardization can accomplish with such data. In methodologies like this, confounders are too numerous to list comprehensively, but just a few - missing data; variability in observations (inter- and intra-observer variability); data originating from different vendor systems with different terminology and definitions, input by myriad people of different backgrounds with differing interpretations of terminologies (students/MD's/RN's etc); different pressures creating bias (time, reimbursement maximization, litigation avoidance); to name just a few.</span><br /><br /><span class="commentBody" data-jsid="text">Several questions: </span><br /><br /><ul><li><span class="commentBody" data-jsid="text">What is the likelihood these results were themselves a chance outcome? Correlation is not proof, especially where n=1. </span></li></ul><ul><li><span class="commentBody" data-jsid="text">How do we reliably identify <i>ante hoc</i> the "</span>types of very large cohort studies" that we can complete?</li></ul><ul><li><span class="commentBody" data-jsid="text">What is the likelihood that such techniques are generalizable to all studies (such as comparative effectiveness research, currently a governmental initiative), especially where issues and confounders might be subtle?</span></li></ul><ul><li><span class="commentBody" data-jsid="text">Related to generalizability <u>supra</u>, where are the scientific studies that prove methodologies like this are valid and reliable for other than, say, low-granularity epidemiological purposes?  Put more colloquially - how do we know what these efforts attempt to do, in what is almost indisputably a radical deviation from controlled-trial norms, is not "computational alchemy" (i.e., attempting to turn lead into gold)?</span></li></ul><ul><li><span class="commentBody" data-jsid="text"></span><span class="commentBody" data-jsid="text">Is there rigorous data on attempted studies like this<i> </i>that<i> failed to correlate</i> with more traditional research?</span>  Unless the latter is studied and/or attempted and some sense gained of whether a radical approach using uncontrolled data such as this does not fail to a concerning extent, <b>then claims of "revolutions" need to be postponed.</b></li></ul><span class="commentBody" data-jsid="text"> <br /> Worst case scenario: large dataset, radical analytics and a political agenda can lead to undesired outcomes.  We need to know what we are doing.</span><br /><br /><span class="commentBody" data-jsid="text">More on these issues in a 2009 article I authored <a href="http://www.jpands.org/vol14no2/silverstein.pdf" target="_blank">here</a>. </span><br /><br /><span class="commentBody" data-jsid="text">I have invited Dr. Kaelber to comment on the questions I raise. </span><br /><br /><b>Note:  </b>I am not challenging this specific study per se, which is an experiment, but <b>am</b> challenging the generalizability of this type of "from data rags to information riches" methodology, as I've done in other posts on similar topics. Not to mention, the overconfidence as expressed in the press, which is what the public including our lawmakers and people responsible for resource allocation read.  I think it's highly premature to write of "revolutionizing medical research."<br /><br />Sep. 4, 2012<br /><br />Here is the reply from Dr. Kaelber -<br /><br /><blockquote class="tr_bq">We actually cover many of the points you raise in the discussion of the article.<br /><br />I think it is important if we are focusing on a scientific discussion of a scientific article to focus on the primary source - the scientific article itself, and not a secondary source - the reporting of the scientific article.<br /><br />One of the major points in the discussion (quoted from the published manuscript) is that we feel that there are three keys to using pooled, standardized, normalized, and de-identified EHR data, including:<br /><br />1. Understanding data sources - understanding of the characteristics of the underlying EHR data sources, including a data dictionary and ontologies used.<br /><br />2. Corroborating data findings - internal and/or external methods to corroborate retrospective EHR cohort study data and/or findings. For example, manual chart review of a sample of the EHR data (internal validation), or other studies demonstrating similar results (external validation), ideally coupled with a biologically plausible hypothesis.<br /><br />3. Clinical data versus research data - recognizing that retrospective EHR data were typically collected for clinical and not research purposes. Therefore, depending on the type of data, the quality may not meet typical research standards. In some cases, the large quantity of clinical data may help mitigate the fact that it was not collected with the higher precision and accuracy that can occur as part of a prospective research study.<br /><br />As I was also quoted in the Plain Dealer article as saying this is like a new type of power drill for those who have been used to using hand drills for retrospective (electronic or paper) chart reviews. To be used appropriately, researchers need to understand the opportunities and disadvantages of using of the new tool and be trained on how to use it.<br /><br />I would also add that, again, as was stated in the introduction for the published paper that clinical research informatics as a field is in its infancy and we need more people involved in the field, more tools for people in the field, and more experience of people using tools in the field to really understand both the contributions and limitations for electronic health record data to advance clinical research.<br /><br />I hope these comments are of some interest/use.<br /><br />-David </blockquote><br />My thoughts are that use of of experimental EHR-based methodologies like this, that could have significant social implications, requires significant caution and validation.  I think we are in agreement on that point.  The methodology of use of EHR data from myriad sources needs to be shown valid, as well as proven <i>not to be invalid</i>, before the findings of "new" studies that are not attempting to duplicate prior ones are translated to the bedside or beyond.<br /><br />The disadvantages include, among other issues (and perhaps most important) the spread of premature over-optimism about health IT such as in newspapers.  That problem has, I believe, contributed greatly to the prevalent <a href="http://hcrenewal.blogspot.com/2012/03/doctors-and-ehrs-reframing-modernists-v.html" target="_blank">hyper-enthusiasm</a> and <i>"there's little supportive data - <b>nevertheless, we believe </b>- so let's spend $15+ billion dollars"</i> attitudes about current health IT as I wrote about, for instance, <a href="http://hcrenewal.blogspot.com/2012/05/oncs-health-data-palooza-title-of.html" target="_blank">here</a> (ONC's 'Data Palooza') and <a href="http://hcrenewal.blogspot.com/2012/08/the-scientific-justification-for.html" target="_blank">here</a> (on MU Stage 2 justifications).<br /><br />Finally, I would question whether increasing the quantity of data could ever reliably compensate for lack of quality (unless, perhaps  the additions were themselves of high quality).  Adding low quality data to already low quality data should not produce better results, it seems to me.<br /><br /><span class="commentBody" data-jsid="text">-- SS</span> <br /><br />

"MetroHealth, Explorys use huge patient database to revolutionize medical research"

As I have written in the past, beware claims of "revolutions" where healthcare or medical research are involved.  As in a slide in my recent presentation to the Health Informatics Society of Australia…

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