healthy4u: pharmaceuticals

The Return of PharmaLot

After an unfortunate hiatus (see<a href="http://hcrenewal.blogspot.com/2014/01/pharmalot-sent-down-memory-hole.html"> this post</a>), <a href="http://blogs.wsj.com/pharmalot/">PharmaLot</a> is back.  PharmaLot was one of the premier sources of incisive information on the pharmaceutical industry, is back.  PharmaLot was and now is run by Ed Silverman, and is known for publishing important, but sometimes unpleasant truths. Ed Silverman provided unbiased, insightful reporting.  Notably for the <a href="http://hcrenewal.blogspot.com/">Health Care Renewal</a> audience, he was not afraid to report on the good, the bad, and the ugly. He was no friend of marketing and public relations smarm.  Often he was first to break stories involving legal settlements, guilty pleas, and miscellaneous misconduct, and in some cases was one of the few to document such stories. For example, when PharmaLot last disappeared, I noted that it provided one of the few accounts of a $21 million fine imposed on Merck by French antitrust regulators (here is the brief <a href="http://www.reuters.com/article/2013/12/19/us-france-fine-idUSBRE9BI0Q420131219">Reuters version</a>.)  PharmaLot reported on a judgement against Actelion for anti-competitive practices in support of its drug for pulmonary artery hypertension.  The only other media report on this was <a href="http://www.sfgate.com/business/article/Actelion-loses-appeal-in-lung-drug-case-5079481.php">in the San Francisco Chronicle</a>, and it was less detailed.  As we have noted endlessly, bad behavior by large health care organizations, including pharmaceutical and biotechnology companies and the various organizations with which they interact, like <a href="http://hcrenewal.blogspot.com/search/label/contract%20research%20organizations">contract research organizations</a>, <a href="http://hcrenewal.blogspot.com/search/label/medical%20education%20and%20communication%20companies">medical education and communication companies (MECCs)</a>, etc has often been <a href="http://hcrenewal.blogspot.com/search/label/anechoic%20effect">anechoic</a>.  If one likes to get along by going along, it is not a good idea to make too much of a fuss about such issues and <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppression</a> and <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation of clinical research</a>, <a href="http://hcrenewal.blogspot.com/search/label/deception">deception</a> in  <a href="http://hcrenewal.blogspot.com/search/label/marketing">marketing</a>, and <a href="http://hcrenewal.blogspot.com/search/label/perverse%20incentives">perverse incentives</a> including the creation of <a href="http://hcrenewal.blogspot.com/search/label/conflicts%20of%20interest">conflicts of interests</a>, much less outright <a href="http://hcrenewal.blogspot.com/search/label/crime">crime </a>and <a href="http://hcrenewal.blogspot.com/search/label/health%20care%20corruption">corruption</a>.  Ed Silverman was known to fuss about such issues. So the return of his fearless reporting, and willingness to post controversial interviews and editorials, is a rare ray of light in the gloom.  PharmaLot has just been added back to our blog roll.  Welcome back! PS - It may be too much to hope that the back archives of older versions of PharmaLot can be restored to public view.  We wait with baited breath.  Hat tips to <a href="http://1boringoldman.com/index.php/2014/06/04/oh-how-weve-missed-our-pharmalot/">1BoringOldMan</a>, <a href="http://loathingbioethics.blogspot.com/2014/06/pharmalot-is-back.html">Fear and Loathing in Bioethics</a>

The Return of PharmaLot

After an unfortunate hiatus (see this post), PharmaLot is back. PharmaLot was one of the premier sources of incisive information on the pharmaceutical industry, is back. PharmaLot was and now is run…

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05 Jun 2014

Some Authoritative Skepticism about the "Triumph" of Sovaldi to Add to Outrage about "Blood Money"

Three weeks ago we posted about the continuing controversy over the stratospheric price of the new antiviral drug for hepatitis C (HCV), sofosbuvir (Sovaldi, by Gilead).  While the amazing $1000 per pill price got deserved attention, at that time no one but your humble blogger seemed to be <a href="http://hcrenewal.blogspot.com/2014/04/knee-deep-in-hoopla-triumph-of-medical.html">publicly skeptical </a>about published assertions that the drug was some sort of modern miracle, and a triumph of medical science.  At that time, we noted that there is no "strong clear evidence that this drug is extremely effective and remarkably safe, i.e., that the drug is a 'triumph' that will cure nearly everyone without risk or harm to them, and therefore warrants a princely price." Since then, two other skeptical opinions have become public. The German Institute for Quality and Efficiency in Health Care (IQWiG) Early Benefit Assessment The German agency performed this assessment based on a dossier submitted by the drug manufacturer (presumably Gilead).  The assessment found some reason to think the drug beneficial, but that the evidence was sparse, left many questions unanswered, and was inadequate to assess the drug for some important patient populations.  At this point, only a <a href="https://www.iqwig.de/en/press/press_releases/press_releases/sofosbuvir_indication_of_added_benefit_for_specific_patients.6099.html">summary</a> is available in English.  It includes links to further information in German. The overall assessment was, <blockquote class="tr_bq">The dossier submitted by the drug manufacturer provides indications of added benefit for non-pretreated patients infected with the virus of genotype 2. However, the extent cannot be quantified. There were no suitable data in the dossier for patients who are infected with other virus types (genotype 1 and 3 to 6) or who are coinfected with HIV.</blockquote>Limited Generalizability Particular problems with data about genotypes other than 2 were: <blockquote class="tr_bq">The manufacturer presented no adequate analyses for infection with type 1 and type 3 to 6 viruses and for <acronym title="human immunodeficiency virus">HIV</acronym> coinfection. It analysed results from studies in which the respective comparator therapy was tested in at least one study arm and compared these in a 'historical' comparison. It included both randomized controlled trials (<acronym title="randomized controlled trial ">RCTs</acronym>) and one-arm studies on the sofosbuvir side, but only <acronym title="randomized controlled trial ">RCTs</acronym> on the comparator side. It justified this by claiming that it wanted to reduce the number of hits of its literature search. However, the database for the comparison was different because of this and the comparison itself was therefore unsuitable. A first literature search by <acronym title="Institute for Quality and Efficiency in Health Care">IQWiG</acronym> showed that a number of studies were not considered in the dossier.</blockquote>Thus the assessment concluded that the drug company dossier included at best irrelevant data that it tried to pass off  as important, and inexplicably left out other data that might have been relevant. Problem with Random Allocation The German assessment focused on the single randomized controlled trial which compared sofosbuvir and ribavirin to peg-interferon and ribavirin whose results were published in the New England Journal and discussed in our previous posts (<a href="http://hcrenewal.blogspot.com/2014/04/knee-deep-in-hoopla-triumph-of-medical.html">here</a> and <a href="http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html">here</a>).   However, the German assessment analyzed what was submitted in the company's dossier about this trial, rather than the published results in the NEJM.  It found problems in addition to those we found, starting with problems with the randomization, <blockquote class="tr_bq">Overall, <abbr title="Institute for Quality and Efficiency in Health Care">IQWiG</abbr> assessed the risk of bias of the FISSION study as high. The main reason was that the manufacturer only included those participants in the analysis who had received at least one dose of the medication they were randomized to. However, particularly in the control arm, where not the new drug, but conventional drugs were administered, some patients refused to have their planned treatment. This is a general problem of open-label studies, where it is known who receives which treatment. This poses the risk that patients discontinue the study prematurely depending on which treatment they were randomized to. This compromises the aim of randomization: the comparability of the treatment groups.  This is exactly what happened in the FISSION study, which may lead to (highly) biased results.</blockquote> Thus, the assessment concluded that the study had a major problem with randomized allocation.  This should be added to the other problems we found: unblinded ascertainment of adverse effects potentially leading to bias, apparently deliberate obfuscation of adverse effects, especially deaths occurring during the trial, and lack of long term followup.  This suggests that the study was manipulated to increase the likelihood of favorable results Failure to Consider Important Outcomes The German assessment also concluded that the trial provided no information about mortality or quality of life benefits, <blockquote class="tr_bq"> As no deaths occurred in the FISSION study in the therapeutic indication genotype 2, there could be no differences between the treatment groups, and therefore no proof of added benefit, in the outcome 'mortality'. This also applies to health-related quality of life, but in this case because the dossier contained no evaluable data for this outcome.</blockquote> Note, however, that this suggests that the data submitted in the dossier was different than that reported in the New England Journal of Medicine.  We <a href="http://hcrenewal.blogspot.com/2014/04/knee-deep-in-hoopla-triumph-of-medical.html">noted</a> that in the supplemental data from the trial available on the web appeared data on mortality.  However, it showed higher (albeit still very minimal) mortality in the sofosbuvir group than in the peg-interferon group. The fact that the dossier submitted in Germany omitted all mortality results should be added to the fact that the NEJM report buried the mortality data in the on-line supplement, increasing the likelihood that the dissemination of this part of the results was manipulated to forestall the questions that it ought to provoke. The German assessment further noted that the dossier included no good data about possible harms or adverse effects of the new drug, <blockquote class="tr_bq">The data on side effects contained in the dossier could only be assessed to a limited extent. The manufacturer presented these data on the basis of the proportions of patients with at least one event. However, this type of analysis is only suitable to a limited extent because the observation period of the patients was different in the two study arms.</blockquote> Note that is suggests another type of study manipulation, unequal assessment of harms in the study arms perhaps meant to minimize the apparent harms of the new drug.   Furthermore, again the data in the dossier appeared discrepant from that in the NEJM article (which we discussed <a href="http://hcrenewal.blogspot.com/2014/04/knee-deep-in-hoopla-triumph-of-medical.html">here</a>), <blockquote class="tr_bq"> Severe adverse events only occurred once in each of the two study arms. A statistically significant difference in the outcome 'treatment discontinuation due to adverse events' in favour of sofosbuvir was not robust in the sensitivity analyses performed by <abbr title="Institute for Quality and Efficiency in Health Care">IQWiG</abbr>. With regard to side effects, <abbr title="Institute for Quality and Efficiency in Health Care">IQWiG</abbr> therefore considers the added benefit as not proven.</blockquote> The severe adverse event rates reported in the New England Journal article were higher, and the reason for this discrepancy is unclear.   A Non-Quantifiable Benefit? So ultimately only a qualitative assessment of the drug's benefits for genotype 2 patients was possible, <blockquote class="tr_bq"> For treatment-naive patients with genotype 2 chronic hepatitis C, an overall positive effect of sofosbuvir in comparison with the appropriate comparator therapy remains with regard to serious secondary diseases. The extent of this added benefit – which was determined with the surrogate '<acronym title="Sustained virological response">SVR</acronym>' – is non-quantifiable, however, because it is unclear how often the development of liver cancer can in fact be prevented. </blockquote> Note that mention of the IQWiG assessment has been made so far in only one major US media outlet, <a href="http://www.bloomberg.com/news/2014-05-02/gilead-s-sovaldi-has-unclear-cancer-benefit-german-agency-says.html">Bloomberg</a>.    The Institute for Clinical and Economic Review Evidence Report This report just appeared online in JAMA Internal Medicine [Ollendorf DA, Tice JA et al.  The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection.  JAMA Inte Med 2014.  Link <a href="http://archinte.jamanetwork.com/article.aspx?articleid=1867174">here</a>.]  The review found again that there were major limitations in the available data, and so much of it was based on a network meta-analysis and simulation studies, <blockquote class="tr_bq">The review was limited to patients with genotype 1, 2, and 3 infections, which account for most HCV cases in the United States. At the time of the review, no head-to-head trials of the direct-acting antiviral drugs had been performed, and most of the data on sofosbuvir came from uncontrolled studies We therefore used network meta-analytic techniques to perform indirect comparisons of sustained virologic response outcomes across treatment options<a class="reflink" href="http://archinte.jamanetwork.com.revproxy.brown.edu/article.aspx?articleid=1867174#iep140001r6" id="archinte.jamanetwork.com.revproxy.brown.edu/article.aspx?articleid=1867174#iep140001r6-scm6MainContent_ucArticleContent_rptSections_lblSection_6"></a> and used these results as the input to a simulation model that compared the estimated clinical and economic outcomes of treatment after 1 and 20 years.</blockquote> It is very hard for me to independently evaluate the credibility of these indirect methods of analysis of what amounts to sketchy data.  However, I should note that Ollendorf et al did not some other specific problems with the available data on sofosbuvir: <blockquote class="tr_bq">Yet at the time of this review there were several reasons for caution. First, the evidence base on the comparative clinical effectiveness of these 2 new drugs remained thin in most areas and notably incomplete in others. For example, in some subgroups, such as patients who have failed earlier treatments, there were little or no data available. There were no long-term data demonstrating the durability of short-term sustained virologic response rates for either drug; nor had either drug been compared head-to-head in a randomized clinical trial with each other or with a first-generation direct-acting antiviral drug. Finally, the evidence necessary for sofosbuvir to gain marketing approval through the FDA’s breakthrough designation was particularly sparse and did not include requirements for controlled trials.</blockquote> Furthermore, it suggested reduced enthusiasm for treatment since most patients with hepatitis C will not develop severe complications, limiting the potential benefits of treatment, <blockquote class="tr_bq"> HCV is an indolent infection, and most adults with this infection will never develop negative health effects during their lifetime. Many people with HCV infection have no evident liver dysfunction. For such patients, the decision about whether and when to initiate treatment should involve careful consideration of the balance of risks and benefits and shared decision-making with experienced clinicians.</blockquote> Note that at least to date, I have seen no discussion of the Ollendorf report in the media. Pricing Unrelated to Production or Research and Development Costs Meanwhile, there has been continued outrage in the media over the pricing of this probably not so miraculous drug.  Some has focused on the likelihood that most of the price represents pure profit, excess marketing (and perhaps huge payments to corporate insiders), rather than production or research and development costs.  For example, Bernard Munos <a href="http://www.forbes.com/sites/bernardmunos/2014/04/16/has-healthcare-embraced-a-hit-and-run-strategy/">wrote</a> in Forbes <blockquote class="tr_bq">To compound the outrage, there is hardly a relationship between drug prices and their actual costs, which makes many patients feel as if they were held to ransom. Gilead, to its credit, has negotiated a deal that makes Sovaldi available to Egyptian patients at a <a href="http://www.fiercepharma.com/story/express-scripts-adds-fuel-fire-fight-over-gilead-sciences-sovaldi/2014-04-09">99% discount</a>, but it may have also bolstered suspicions of profiteering.</blockquote> Similarly, Julian Urrutia <a href="http://blogs.law.harvard.edu/billofhealth/2014/04/13/you-cant-put-a-price-tag-on-sovalid-unless-its-over-84k/">wrote</a> in the Bill of Health blog from the Harvard Law School Petrie-Flom Center, <blockquote class="tr_bq">Gilead is working to offer lower prices in dozens of developing countries (of the 150 million patients with HCV, only about 1% are in the USA). <div style="text-align: justify;">To me, this implies one of two things. Either Gilead will be selling the drug in developing countries at a price that allows it to make normal profits (in which case Gilead is capturing enormous rents in the USA market from $84K price tag), or whoever pays for the treatment of patients with HCV in developed countries will be subsidizing the treatment of patients in the developing world.</div></blockquote><div style="text-align: justify;"> </div><div style="text-align: justify;"></div> The Editor of Modern Healthcare, Merrill Goozner <a href="http://www.modernhealthcare.com/article/20140503/MAGAZINE/305039983">wrote</a>, an analysis of how Gilead's immense revenue was built on US government funded research, and academics who could privatize the research they did with such funding on university time, <blockquote class="tr_bq"> The National Institutes of Health invested heavily in university-based scientists to understand the genetic weak points of hepatitis C, just as it did for HIV. It gave grants to build virology labs, come up with potential drugs and conduct clinical trials. One of those scientists was Raymond Schinazi, director of the Laboratory of Biochemical Pharmacology at the Emory School of Medicine in Atlanta. During the past 20 years, Schinazi's laboratory received at least $7.7 million from the National Institute of Allergy and Infectious Diseases. He wasn't alone. Some, like Kevin Raney, chair of the biochemistry and molecular biology department at the University of Arkansas for Medical Sciences, even developed drugs on their government grants, although his never made it into clinical trials. Schinazi, a serial entrepreneur, took a different path. In the late 1990s, he formed the pharmaceutical company Pharmasset, to develop an antiviral drug invented at Emory. The company also worked on cures for HIV and hepatitis B. The original drug candidate went nowhere, he told me in a telephone interview. But chemists working inside Pharmasset—at the time of its sale to Gilead in 2011 it had only 82 employees—developed several novel therapeutics for the diseases, including one that eventually became Sovaldi. Securities and Exchange Commission filings for Pharmasset during its years as a stand-alone research and development company revealed it spent under $7 million on R&D in 2003. In its early years, it received $1 million in government grants. Its total losses through 2011 came to $314.8 million. It was also investigating drugs for HIV and hepatitis B throughout that period. The company hit the jackpot with hepatitis C and Sovaldi though, which led Gilead, whose initial success came from HIV drugs, to pay $11 billion for the company. Schinazi, who had retained a sizable stake in the firm after cutting his ties in 2006, walked away with over $400 million, according to a published report. Gilead spent tens of millions of dollars to complete Sovaldi's clinical trials. Yet last August, the NIAID issued a news release touting its role in running one of those trials when positive results were reported in JAMA. The government, it turns out, had kept its hand in the development of Sovaldi.</blockquote> So it appears that the pricing of Sovaldi has almost nothing to do with production or research and development costs.  Much of the initial research needed to develop Sovaldi was underwritten by the government.  Gilead paid royally for the results of the research, but most of the money went to investors and executives, including the former academic who did some early development work on government money and became tremendously rich from Gilead's largesse. Growing Outrage over Extortionate Behavior Some has focused on how the price represents unethical, if not extortionate behavior by corporate executives.  For example, Munos also wrote, <blockquote class="tr_bq">What has changed is perhaps the fact that the industry no longer realizes – or accepts – that it has a covenant with society. This is no ordinary business as it can only operate by the will of the people. Drug makers get intellectual property rights, which are essentially a license to print money, but in exchange society expects affordable innovation. For most of the past century, that bargain has worked remarkably well. But, if drug companies fail to live up to it, society can also revisit its part, and scale back patent rights, or deny reimbursement. And this is happening in a rapidly-growing list of countries – not just India and China, but Germany, the UK, France, Canada, and soon… coming to a drugstore near you. The legendary leaders who built the pharmaceutical industry as one of the most respected understood that bargain. One remembers George <a class="exit_trigger_set" href="http://www.forbes.com/companies/merck/">Merck's</a> <a href="http://books.google.com/books?id=A99WFv8v8bkC&pg=PA93&lpg=PA93&dq=%22george+merck%22+%22Medicine+is+for+the+people.+It+is+not+for+the+profits%22&source=bl&ots=_ziwZk3lLM&sig=KhWStbwfjWoBFpjB5sH7Ha8A1Zw&hl=en&sa=X&ei=FLZLU86SL4bhyQG4nIGwBQ&ved=0CE0Q6AEwBA#v=onepage">admonition</a> ('Medicine is for the people. It is not for the profits'), Jonas Salk’s quaint <a href="https://en.wikipedia.org/wiki/Jonas_Salk">remark</a> about the polio vaccine patent, Robert Wood Johnson’s <a href="http://www.jnj.com/about-jnj/jnj-credo/">Credo</a>, and Roy Vagelos’ more recent <a href="http://knowledge.wharton.upenn.edu/article/roy-vagelos-talks-about-leadership-and-the-need-for-new-drug-pricing-policies/">warning</a> about the industry’s ill-conceived pricing policies.  They understood that self-policy is always better than regulation, and such moderation served them well. But their successors’ failure to uphold their advice has led to an onslaught of regulations and policy changes that threatens to permanently remake the industry.</blockquote> Elisabeth Rosenthal <a href="http://www.nytimes.com/2014/04/27/sunday-review/it-will-save-lives-but-whats-the-cost.html">wrote</a> in the NY Times, quoting Steve Francesco, a pharmaceutical consultant, <blockquote class="tr_bq">'To understand drug pricing you have to shed your sense of value as a consumer and as a noble human being,' Mr. Francesco said. 'You have to put on the lens of the health care industry, where what you’re doing is looking for opportunities to maximize return.'</blockquote> Also in Forbes, Dr Robert Pearl <a href="http://www.forbes.com/sites/robertpearl/2014/04/24/americas-broken-health-care-system-the-role-of-drug-device-manufacturers/">wrote</a> this about Sovaldi pricing, <blockquote class="tr_bq"> But at $1000 a pill, its pricing is exorbitant, monopolistic, and disrespectful to the purchasers and patients who will bear the brunt of the massive cost.</blockquote> Dr Frank Huyler <a href="http://www.nydailynews.com/opinion/life-worth-article-1.1761457">wrote</a> in the New York Daily News about blood money, <blockquote class="tr_bq">This sort of blood money is nothing new. But it is among the worst of recent examples; yet another evil act, yet another predation on mostly poor, mostly desperate people, who inevitably will ask taxpayers to save them.</blockquote><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">Summary</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">It is even bloodier money if the assumption that the drug is a "well-tolerated and effective cure," which  Dr Huyler held, proves not to be true.  It is clear that most of the money that Gilead is now scooping up in the US is not to pay retrospectively for research and development or drug production. Instead, it seems likely to be supporting marketing, public relations, some investors' profits, and huge executive compensation.  When the public realizes that the money may not be buying miracles, the outrage should increase.  </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">The Sovaldi case is a signal example of how our health care system is awash in marketing hype and public relations buzz that has swamped rational skeptical thinking about logic and evidence.  That marketing and PR is ever enriching managers while it will send the rest of us, health care professionals included, to the poor house.  And all the money we spend will not buy us the promised miracles and triumphs.  </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">True health care reform would revisit the pact society once made with drug, biotechnology and device companies meant to promote reasonably priced innovation, but now promoting oligarchy; support transparency and honesty in clinical research; and challenge how health care managers can make millions or billions from unproven, and sometimes worthless or dangerous products. </div>

Some Authoritative Skepticism about the "Triumph" of Sovaldi to Add to Outrage about "Blood Money"

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07 May 2014

Knee Deep in the Hoopla - "A Triumph of Medical Technology" Sans Evidence of Superiority from Published Randomized Double Blind Controlled Trials

With the publication of several new articles in the prestigious New England Journal of Medicine, the buzz about Sovaldi (sofosbuvir - Gilead), a new oral treatment of hepatitis C, has become feverish.  The drug had been hailed as near miraculous, and the only debate has been about its near stratospheric cost (look <a href="http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html">here</a>).  This week, of all weeks, however we should be extremely skeptical about expensive drugs promoted as the cures of our most feared ills.  This week a series of articles appeared in the British Medical Journal showing that there was no evidence to support the clinical value of the  antiviral drugs stockpiled for governments as proof against dreaded influenza epidemics (look <a href="http://www.bmj.com/content/348/bmj.g2695">here</a> to start).   The Latest Buzz As we <a href="http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html">posted earlier</a>, the discussions contrast the ostensibly near miraculous aspects of the drug's performance with its extremely high price.  For example, a few days ago the Los Angeles Times <a href="http://www.latimes.com/science/la-sci-hepatitis-c-cure-20140412,0,3083638.story">reported</a>, <blockquote class="tr_bq">In a series of clinical trial results, a new generation of antiviral medications was able to clear the liver-ravaging virus from virtually all patients' bloodstreams in as little as eight weeks. Even in patients with the most stubborn infections, the new drugs were capable of suppressing the virus completely at rates well over 90%. The treatments, however, come with a steep price tag.</blockquote> So, <blockquote class="tr_bq">The new medications are 'a triumph of modern medical technology,' said Dr. Jeffrey Tice, a UC San Francisco physician who was not involved in any of the clinical trials.</blockquote> Accompanying the research reports in the New England Journal was a commentary by Dr Raymond T Chung and Dr Thomas F Baumert.  Its title proclaimed Sovaldi and similar drugs also to be part of "The Arc of Medical Triumph."(1)  Buried in the commentary's <a href="http://www.nejm.org/action/showSupplements?doi=10.1056%2FNEJMp1400986">supplementary material</a> was a<a href="http://www.nejm.org/doi/suppl/10.1056/NEJMp1400986/suppl_file/nejmp1400986_disclosures.pdf"> link</a> to disclosure forms that showed that: <blockquote class="tr_bq">Dr Chung reports grant support from Gilead Sciences [the manufacturer of Sovaldi], Mass Biologics, Vertex and Merck, and personal fees from Abbvie, Enanta and Idenix.</blockquote> Note that Abbvie and Merck are also at work on antiviral treatments for hepatitis C. and <blockquote class="tr_bq">Dr Baumert reports several patents ... and pending patents [apparently that could be conflicts of interest] </blockquote> It is clear that there have been major scientific advances in the characterization of the hepatitis C virus, and development of multiple new antiviral agents which promise to treat that infection.  Furthermore, clearly there is reason for hope for treatment of hepatitis C that prevents its long-term complications and averts premature death. (Of course, that hope could be a bit stronger in the hearts of those who have financial relationships with the corporations that stand to profit from sales of these drugs.) But it is not obvious that there is sufficient clear evidence from clinical research, particularly from double-blind randomized controlled trials (RCTs), that shows the newest treatments will provide triumphal benefits to patients that outweigh their possible harms. One Published Unblinded RCT Compared Sovaldi to Peg-Interferon In our <a href="http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html">previous post</a>, written after the immense price of the new drug in the US became apparent, we questioned whether the evidence from controlled trials then available would justify the hype, and the high price. We looked at what appeared to be the then single best available study. The <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1214853">most prominent randomized controlled trial of Sovaldi for patients who had not had previous therapy for hepatitis C</a> that had been published by March, 2014, appeared in the New England Journal of Medicine in May, 2013.(2)   While it provided some reason for hope, it did not provide clear evidence that Sovaldi was a miracle drug. The study showed that Sovaldi plus ribavirin produced the same rate of sustained virologic response (SVR), 67%, as did the previously accepted standard treatment, peg-interferon plus ribavirin, again 67%.  (SVR means that the hepatitis C virus has become undetectable in the patient's blood, and is believed, but not proven to represent a cure.) While Sovaldi had lower rates of unpleasant side effects than did peg-interferon, these rates were not negligible. For example, the rate of nausea after peg-interferon was reported to be 29%, but after Sovaldi it was still 18%.  Given that the trial was unblinded, and that some of these side effects have a subjective element, these figures could have been biased due to patient expectations that the new drug would have fewer side effects. Furthermore, Sovaldi appeared to produce higher rates of severe adverse effects (3%) than peg-interferon (1%).  However, the article did not mention any deaths in either treatment group.  When I later reviewed the  <a href="http://www.nejm.org/doi/suppl/10.1056/NEJMoa1214853/suppl_file/nejmoa1214853_appendix.pdf">supplemental data</a> available on the web from the May, 2013 article, I found that buried within this information were the facts that two people died during treatment with Sovaldi, and one after treatment with peg-interferon.  So, the rate of  severe adverse effects or death after Sovaldi treatment was more than double (9/256 ) than that after peg-interferon (4/243).  It is very curious and concerning that the authors chose not to mention deaths of study subjects in the paper that reported their trial results.    Finally, the trial, like just about all previous trials of treatment of hepatitis C, did not follow patients long-term, and hence could not show whether treatment actually resulted in better clinical outcomes, for example, longer survival, decreased rates of severe liver disease, etc.  We thus concluded that there really was no clear evidence that Sovaldi was really a miracle drug, which could cure more people, in fact, nearly everyone, compared to standard therapy, yet with fewer side effects and more safety. Any Evidence from Other Controlled Trials? We looked through the newly published articles, the articles they cited, and the official US label for sofosbuvir to see if there is any other evidence from controlled trials to support the triumphant claims about sofosbuvir.  To simplify this casual, not systematic review, we only looked at articles about patients who had not been previously treated for hepatitis C. The <a href="http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/ucm377920.htm">drug label</a> mentioned a controlled trial that compared sofosbuvir to placebo.  The POSITRON study (study 107) was a trail that compared Sovaldi and ribavirin to placebo in patients who are "interferon intolerant, ineligible or unwilling."  The overall SVR in the treated group was 78%.  The label did not mention adverse effects rates in this trial, and as far as I can tell, it was not published.  Again, while the SVR was good, it was NOT over 90%.  As far as I could tell, the results of this study have not otherwise been published.  The new studies in the New England Journal, and the studies cited by one of them were NOT double-blind randomized controlled trials of sofosbuvir versus some other treatment, or versus placebo for that matter. For example, the study by Afdhal et al in the New England Journal considered sofosbuvir in combination with another new drug from Gilead, ledipasvir.  However, this was an open label (unblinded) study that compared patients given different durations of treatment with both sofosbuvir and ledipasvir with or without ribavirin.  It did NOT directly compare sofosbuvir (or ledipasvir) to any other treatment, or to placebo.(3) Another study by Sulkowski et al in the NEJM focused on previously treated patients. Cited by Afdhal et al were studies by Osinusi et al (an unblinded study that compared different doses of ribavirin given to patients also who all received sofosbuvir)(4); Lawitz et al (an unblinded study that compared different durations of treatment for both sofosbuvir and ledipavir with or without ribavirin)(5); and Gane et al (a study that compared various drugs again all added to sofosbuvir)(6).  Again, NO study compared sofosbuvir to any other treatment, or to placebo. Thus so far I have been unable to find any additional studies that compared Sovaldi (sofosbuvir) to any other potential treatments for hepatitis C.  Without a comparison to another treatment, it is not possible to tell whether the high rates of patients whose blood tests show no detectable hepatitis C virus in the short-term after treatment were due to the excellence of the treatment, or due to selection of patients with particularly good prognoses.   Recall that there is evidence that some patients with hepatitis C spontaneously clear their blood of hepatitis C, and become spontaneously cured (see our <a href="http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html">previous discussion</a>, and particularly the study by Seeff et al[7]).  There is evidence that the studies above may have been designed to only include patients with the best prognoses.  They generally were designed with very complicated, restrictive and subjective inclusion and exclusion criteria that could have eliminated all but the healthiest patients.  For example, according to the <a href="http://www.nejm.org/doi/suppl/10.1056/NEJMoa1402454/suppl_file/nejmoa1402454_protocol.pdf">study protocol</a> found in the <a href="http://www.nejm.org/action/showSupplements?doi=10.1056%2FNEJMoa1402454">supplementary material</a> for the study by Afdhal et al, patients with "clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol" would have been excluded, as would have "subjects currently under evaluation for a potentially clinically-significant illness (other than HCV)...." So, while many articles about sofosbuvir (Sovaldi) have appeared recently, in my humble opinion they do not provide strong clear evidence that this drug is extremely effective and remarkably safe, i.e., that the drug is a "triumph" that will cure nearly everyone without risk or harm to them, and therefore warrants a princely price. Summary While the buzz about Sovaldi intensifies, there still seems to be little clear evidence to justify extravagant claims made for it, or the extravagant price demanded for it.  Yet there seems to be a bandwagon building to somehow pay whatever it takes to provide the "triumph" of medical science to every patient who needs it.  At the current price, that should make the CEO of Gilead even richer (increases in the stock price after the $84,000/ course drug price was announced already turned him into a billionaire on paper, look <a href="http://www.bloomberg.com/news/2014-03-03/gilead-ceo-becomes-billionaire-on-84-000-hepatitis-drug.html">here</a>.)  As noted above, it is not clear what benefits such a costly policy would bring to patients, and at what risks. We have discussed how our current policy of letting corporations sponsor and run the clinical research meant to assess their own products has lead to widespread <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulation of research</a> to make their products look better, and sometimes <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppression of research</a> that cannot be manipulated into making their products look good.  This should make health care professionals, policy makers, and the public extremely skeptical of every over-hyped new "innovation."  So far, there seems to be no public skepticism about this latest, and seemingly most expensive pharmaceutical "triumph." The US health care system, and to some extent the health care systems in most developed countries are experiencing ever higher prices.  Much of these prices' effects seem to drive up remuneration of health care executives and managers, but whether they buy better care or outcomes for most people is not so clear.  The ever rising prices seem to be buoyed by endless enthusiasm for new tests, treatments, programs, and unbridled faith in the benefits of all new technology.  It is not clear how much of that is due to evidence, how much is based on ideology and unquestioning faith in technological progress, and how much is driven by marketing and public relations, which not always may be entirely honest and free from deception. Evidence-based medicine rigorously applied suggests that individual health care and health policy decisions should be driven by the best available evidence, mostly from clinical research, about the benefits and harms of tests, treatments, programs, and so on, in the context of what outcomes matter to patients.  The skepticism EBM should engender could lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism. If only such skepticism were easier to find. References 1.  Chung RT, Baumert TF.  Curing chronic hepatitis C - the arc of medical triumph.  N Engl J Med 2014:  Link<a href="http://www.nejm.org/doi/full/10.1056/NEJMp1400986"> here</a>. 2.   Lawitz E, Mangia A, Wyles D et al.  Sofosbuvir for previously untreated chronic hepatitis C infection.  N Engl J Med 2013; 368: 1878-1887.  Link <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1214853">here</a>. 3.  Afdhal N et al.  Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.  N Engl J Med 2014: Link<a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1402454"> here</a>. 4.  Orinusi A Meissner EG, Lee YJ et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial.  JAMA 2013; 310: 804.  Link <a href="http://jama.jamanetwork.com/article.aspx?articleid=1733720">here</a>. 5.  Lawitz E, Poordad FF, Hyland RH et al.  Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised phase 2 trial.  Lancet 2013; 383: 515.  Link <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2962121-2/abstract">here</a>. 6.  Gane EJ, Stedman CA, Hyland RH et al.  Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection.  Gastroenterology 2013.  Link <a href="http://www.ncbi.nlm.nih.gov/pubmed/24262278">here</a>. 7.  Seeff LB, Hollilnger B, Alter HJ et al.  Long-term mortality and morbidity of transfusion- associated non-A, non-B, and type C hepatitis: a National Heart Lung and Blood Institute Collaborative Study.  Hepatology 2001; 33: 455-463.  Link <a href="http://www.ncbi.nlm.nih.gov/pubmed/11172349">here</a>. ADDENDUM (21 April, 2014) - Also see the post on "breakthrough cures?" by Dr Howard Brody <a href="http://brodyhooked.blogspot.com/2014/04/breakthrough-cures-reasons-for.html">on the Hooked: Ethics, Medicine and Pharma blog</a>.

Knee Deep in the Hoopla - "A Triumph of Medical Technology" Sans Evidence of Superiority from Published Randomized Double Blind Controlled Trials

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16 Apr 2014

Finally, An Article in a Large Circulation Medical Journal with Systematic Data about Leaders of Academic Medicine Conflicted by their Service on Health Care Corporate Boards

Background - a New Species of Conflict of Interest Since <a href="http://hcrenewal.blogspot.com/2006/03/new-species-of-conflict-of-interest-in.html">2006</a>, we have posted repeatedly about  what was then a new species of severe <a href="http://hcrenewal.blogspot.com/search/label/conflicts%20of%20interest">conflicts of interest</a>.  This occurs when leaders of academic medical institutions or other health care non-profit organizations or non-governmental organizations (NGOs) also serve as members of <a href="http://hcrenewal.blogspot.com/search/label/boards%20of%20directors">boards of directors</a> of for-profit corporations  whose products and actions have major effects on health care. Most recently, we <a href="http://hcrenewal.blogspot.com/2014/03/american-board-of-internal-medicine.html">discussed </a>the cases of the current CEO of the National Quality Forum and past CEO of the American Board of Internal Medicine who was found to be on the board of for-profit hospital group purchasing organization Premier Inc, and had been on the board of its privately held but for-profit predecessors.  We then <a href="http://hcrenewal.blogspot.com/2014/02/incoming-president-of-iom-outed-as.html">discussed</a> the case of the incoming president of the US Institute of Medicine and former Chancellor of Health Affairs at Duke University who was on the boards of Alnylam Pharmaceuticals, Medtronic and Pepsico.  We next <a href="http://hcrenewal.blogspot.com/2014/03/turnabout-is-fair-play-why-university.html">discussed</a> the case of the current Dean of medicine at the University of Illinois who is on the board of Novartis.  We also recently <a href="http://hcrenewal.blogspot.com/2014/03/better-late-than-never-jama-article.html">posted</a> about the first time these sorts of severe conflicts of interest issue have been addressed in a large circulation medical journal.  A commentary in JAMA called for many such conflicts to be banned. A Small Study of the Prevalence of a New Species of Conflict of Interest Now JAMA has just published a research letter which examined the prevalence of board members of large, for-profit, publicly held pharmaceutical companies who also were among the leadership of academic medical centers. [Anderson TS, Dave S, Good CB et al. Academic medical center leadership on pharmaceutical company boards of directors.  JAMA 2014; 311: 1353-5.  Link <a href="http://jama.jamanetwork.com/article.aspx?articleid=1853147">here</a>.] The authors looked at public data about 2012 board membership of the 47 biggest publicly held companies based on global prescription drug sales. They tabulated those who were also leaders at (apparently only US) academic medical centers.  The most important findings were: - 19/47 companies (40%) had at least one board member who was a leader of an academic medical center (AMC) - 16/17 US based companies had at least one board member who was also a leader of a US AMC -  pharmaceutical company board members included 2 university presidents, 6 deans of medicine, 6 hospital or health system executives, 7 clinical department chairs or center directors -  28 board members were also members of boards of trustees or directors of US hospitals, medical schools, or their parent universities. Comments We have been trying to raise awareness of this issue since 2006.  Now we have some idea of the size of the problem. Keep in mind that this study did not attempt to determine the prevalence of academic medical center leaders on boards of smaller pharmaceutical companies, privately held companies, biotechnology or device companies, or other health care and health care related companies (e.g., for-profit hospital systems, health insurance companies, for-profit contract research organizations, for-profit medical education and communication companies, large companies with major health care components, etc, etc, etc)  It also did not attempt to determine the prevalence of leaders of other important health care non-profit organizations (e.g., hospitals and hospital systems, insurance companies, professional societies, patient advocacy groups, accrediting boards, etc, etc, etc) on health care or related corporate boards.  It also did not address leaders of health care organizations outside of the US.  So this study likely greatly underestimates the overall prevalence of and the number of people involved in what we first called a "new species of conflict of interest." But it is a start.  And publishing it in JAMA will begin to make more health care professionals, policy makers, and researchers, and more of the public at large aware of the problem. As I said before, it is very nice to see that the issue of what we once called a new species of conflict of interest finally has made the big time.  Whether it now gets any more traction remains to be seen.  Unfortunately, since conflicts of interest can be so profitable for the directly affected parties, I fully expect they will continue to oppose any restrictions.  The money they have made will likely be used to deploy marketing and public relations personnel and legal counsel to counter any attempts to try to make this aspect of health care more honest. As we have said again and again, the web of conflicts of interest that is pervasive in medicine and health care is now threatening to strangle medicine and health care.  Furthermore, this web is now strong enough to have effectively transformed US health care into an oligarchy or plutocracy.  Health care is effectively run by a relatively small group of people, mainly professional managers plus a few (lapsed?) health care professionals, who simultaneously run or influence multiple corporations and organizations. For patients and the public to trust health care professionals and health care organizations, they need to know that these individuals and organizations are putting patients' and the public's health ahead of private gain. Health care professionals who care for patients, those who teach about medicine and health care, clinical researchers, and those who make medical and health care policy should do so free from conflicts of interest that might inhibit their abilities to put patients and the public's health first. Health care professionals ought to make it their highest priority to ensure that the organizations for which they work, or with which they interact also put patients' and the public's health ahead of private gain, especially the private gain of the organizations' leaders and their cronies. ADDENDUM (3 April, 2014) - see also comments by Paul Levy <a href="http://runningahospital.blogspot.com/2014/04/how-not-to-set-example.html">on the Not Running a Hospital blog</a>, <a href="http://1boringoldman.com/index.php/2014/04/01/at-first-glance/">on the 1BoringOldMan blog</a>, and by Ed Silverman (welcome back!) on <a href="http://blogs.wsj.com/corporate-intelligence/2014/04/01/why-people-who-influence-reseach-are-popular-in-pharma-boardrooms/">the WSJ Corporate Intelligence blog</a>.

Finally, An Article in a Large Circulation Medical Journal with Systematic Data about Leaders of Academic Medicine Conflicted by their Service on Health Care Corporate Boards

Background - a New Species of Conflict of Interest Since 2006, we have posted repeatedly about what was then a new species of severe conflicts of interest. This occurs when leaders of academic med…

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03 Apr 2014

Too Good to be True - Sovaldi Kerfuffle Focuses on Price, While Ignoring Limits of Evidence about Effectiveness and Safety

There seems to be rising skepticism about the prices we pay for the latest drugs, devices, and health care programs, especially in the US.  However, our faith in the near miraculous properties of the newest technology appears to go on unabated.  Skepticism, driven by the rigorous thinking that ought to be engendered by the dutiful application of the principles of <a href="http://hcrenewal.blogspot.com/search/label/evidence-based%20medicine">evidence-based medicine</a>, is rarely in evidence. The latest example is of how concern about the sky high price of one new medication seems to have eclipsed any skepticism about how much good that medicine may do for patients. The Sovaldi Pricing Kefuffle Starting in early March, 2014, a media discussion began about the extremely high price set for a new drug for the treatment of hepatitis C.  As first<a href="http://www.washingtonpost.com/national/health-science/costly-hepatitis-drug-sovaldi-rattles-industry/2014/03/01/86cab0b4-a091-11e3-9ba6-800d1192d08b_story.html"> reported</a> by the Washington Post, <blockquote class="tr_bq">When the Food and Drug Administration approved a medication called Sovaldi [sofosbuvir, Gilead] in December, it was hailed as a breakthrough in the fight against hepatitis C, a blood-borne disease that affects 3.2 million Americans and kills more people in the U.S. annually than AIDS. Then California-based Gilead Sciences, the manufacturer, announced the price: $84,000 for a 12-week course, more than what many cancer treatments cost in a year. </blockquote> The coverage focused on whether the price could possible be justified, while it generally conceding that the drug was a huge advance that was genuinely valuable. For example, the Post article noted, <blockquote class="tr_bq">The drug has also prompted a new round of hand-wringing over a larger issue: the escalating cost of specialty drugs, which are designed to treat chronic illnesses such as rheumatoid arthritis and multiple sclerosis and sometimes require special handling. While these therapies are delivering body blows to some of the world’s most pernicious diseases, they also are testing the limits of what society is willing to pay for sought-after treatments or cures. </blockquote> The articles justified the drug's value with several assertions: Sofosbuvir cures nearly everyone of hepatitis C For example, the Post article stated, <blockquote class="tr_bq">Sovaldi promises to cure nearly all sufferers... </blockquote> Similarly, a report by the authoritative <a href="http://www.kaiserhealthnews.org/stories/2014/march/03/insurers-debate-who-should-get-costly-hepatitis-c-drug.aspx">Kaiser Health News</a> stated that the drug has, <blockquote class="tr_bq">a success rate of better than 90 percent.</blockquote> A Bloomberg<a href="http://www.bloomberg.com/news/2014-03-03/gilead-ceo-becomes-billionaire-on-84-000-hepatitis-drug.html"> article</a> quoted Dr Leonard Berkowitz, chief of infectious disease as Brooklyn Hospital Center as saying the drug is <blockquote class="tr_bq">producing 'spectacular improvements' in cure rates....</blockquote> Going even farther, a Denver Post <a href="http://www.denverpost.com/news/ci_25275400/hepatitis-c-breakthrough-drug-sovaldi-promises-high-cure">article</a> quoted Dr Greg Everson, a hepatologist at the University of Colorado, <blockquote class="tr_bq">The word is cure.  To me, the cure of hep C is one of the most significant medical developments of the last 50 years.</blockquote> Sofosbuvir is extremely safe and has few side effects For example, the Post article stated Sovaldi is <blockquote class="tr_bq">a once-daily pill that has far fewer side effects [than other treatments] </blockquote> The Bloomberg article again quoted Dr Berkowitz as saying the drug has <blockquote class="tr_bq">minimal toxicity</blockquote> The Denver Post quoted Dr Everson, <blockquote class="tr_bq">the side effects are almost nonexistent - mild headache and fatigue.</blockquote> Without treatment, hepatitis C leads to very bad outcomes For example, the Post article stated, <blockquote class="tr_bq">The disease can go undetected for years and can eventually lead to cancer or cirrhosis of the liver. </blockquote> Kaiser Health News added, <blockquote class="tr_bq">If left untreated, hepatitis C can cause liver damage over the course of decades. </blockquote> An<a href="http://articles.latimes.com/2014/mar/09/business/la-fi-hepatitis-c-drug-costs-20140310"> article</a> in the Los Angeles Times noted, <blockquote class="tr_bq">Left unchecked, some hepatitis C infections result in liver damage, liver cancer or death.</blockquote> The Denver Post again quoted Dr Everson, <blockquote class="tr_bq">It's a devastating disease. [Also,] It can smolder for years without symptoms, then it destroys the liver - cirrhosis, cancer.</blockquote> Sofosbuvir prevents nearly all these bad outcomes. This was more implied by the media than directly stated, although the Los Angeles Times did quote an executive vice president of Gilead, the manufacturer of Sovaldi, <blockquote class="tr_bq">Sovaldi ... results in very high cure rates that can avoid future costs related to disease progression or treatment failure....</blockquote> Only the New York Times provided just a hint of skunk odor at the garden party.  Its later <a href="http://www.nytimes.com/2014/03/22/business/lawmakers-attack-cost-of-new-hepatitis-drug.html">article</a> on some US congress members' attempt to investigate the pricing of Sovaldi contributed, But most people with hepatitis C never experience serious liver problems.  So many people would be fine without treatment. That little bit of odor notwithstanding, one could ask what is not to like about this drug.  But the coverage really focused on how many people felt the cost was still just too high.  Unstated, but again implied was the notion that these complaints were just sour grapes.  How could anyone begrudge a mere $84,000 for a safe, extremely effective curative drug that would prevent severe morbidity and premature death, yet cause almost no significant side effects? The problem is that the evidence that actually supports the "value proposition" for Sovaldi is actually not clear at all.  The bigger problem is that so far, discussion of this evidence in the media seems to be absent. The Evidence about Treatment of Hepatitis C Let us consider the assertions above, and what evidence there may be to support them,  in slightly different order. Without treatment, hepatitis C leads to very bad outcomes The earliest research on hepatitis C focused on patients who already had severe complications of the disease.  Thus, as Seeff et al wrote in 2000(1), <blockquote class="tr_bq">retrospective studies of person who have chronic, clinically obvious HCV infection may overemphasize more serious outcomes because they risk omitting persons with subclinical infection as well as those in whom infection spontaneously resolves.</blockquote> Yet popular conceptions of hepatitis C, especially those reflected by the current Sovaldi pricing kerfuffle, seem to reflect only the experience of the most unfortunate hepatitis C patients.  In contrast, studies that have followed cohorts of patients who have evidence of early hepatitis C infection show very different results. In 1999, Kenny-Walsh and colleagues reported a cohort of 390 women who had tested positive for hepatitis C after receiving infected immune globulin.(2)  They were able to follow them for 17 years.  In that time period, 43% of the women had no or minimal inflammation of the liver; 49% had no evidence of liver fibrosis; and only 2% had developed fibrosis. In 2000, Seeff and colleagues reported 45 years of follow up of young military men who were found to have evidence of hepatitis C infection from analysis of long stored frozen serum.  Only one (less than 3%) of their admittedly small cohort of 34 positive men had been found to have any sort of liver problem in that time period.(1) In 2001, Seeff and colleagues reported 20-year follow up of several cohorts including 222 patients who developed hepatitis characterized by abnormal liver enzymes after blood transfusion and for whom retrospective tests on stored blood revealed hepatitis C at that time.(3)  The total mortality over 20 years of the hepatitis C patients was not greater than a group of control patients who had been transfused but did not develop clinical hepatitis.  51% of the hepatitis C infected patients had no evidence of chronic hepatitis.  23% had no evidence of continuing hepatitis C infection. These admittedly old studies show that a significant minority of patients with hepatitis C infection spontaneously resolve their infections, and that a majority of patients have no evidence of significant liver disease over decades of observation.  Cirrhosis is actually a relatively rare outcome of hepatitis C infection, and there is no clear evidence that hepatitis C infection increases total mortality. Of course, once a patient with hepatitis C has been unfortunate enough to develop clear liver disease, that patient's prognosis is not so good. Thus, there is no clear evidence that the majority of patients with hepatitis C infection could benefit from anti-viral treatment given prior to development of any significant complications of the infection, because the majority of such patients may never develop any adverse effects of the infection.  Thus it is not at all obvious that any current hepatitis C treatment could be widely life-saving. Treatment Prevents Nearly All Bad Outcomes There have been no long-term randomized controlled trials of any anti-viral treatment for hepatitis C that evaluated clinical outcomes like cirrhosis, liver failure, liver cancer, need for transplantation or death.  All trials of all agents have been relatively short term, and focused on reduction or elimination of detectable virus from the blood as an outcome.  As detailed in the latest evidence report from the US Preventive Services Task Force,(4) there have been observational studies that compared patients who were treated and had sustained virological responses (elimination of detectable virus from the blood) and those who did not in terms of long-term outcomes.  Such observational studies are liable, however, to confounding.  Patients who are willing to take treatment, fully comply with treatment, and respond better to therapy may be systematically different from those who refuse treatment, do not adhere to treatment, or whose treatment is not initially successful.  Most of these studies were considered to be of poor methodological quality, although the best, still only considered of fair quality, did show an association between virological responses and clinical outcomes.  There have been no studies of the comparative effectiveness of different anti-viral treatments. Thus, the evidence that anti-viral treatment for hepatitis C prevents any bad clinical outcomes, like cirrhosis, liver failure, liver cancer, or premature death is unclear. Now to consider the best evidence available about sofosbuvir. Sofosbuvir cures nearly everyone of hepatitis C So far, the best study reported about sofosbuvir seems to be one in the New England Journal of Medicine in 2013.(5)  This report included an open-label (not blinded) controlled trial called FISSION of sofosbuvir plus ribivirin versus peginterferon alfa-21 plus ribivirin.  Its primary outcome measure was viral response 12 weeks after therapy (which lasted 12 weeks in the first group, 24 in the second).  The proportion of patients with responses 12 weeks after therapy were 67% in both groups.  Patients who received sofosbivir had lower rates of the common, uncomfortable complications attributed to interferon therapy than those who received peginterferon (e.g., fatigue, 36% versus 55%; nausea, 18% versus 29%).  However, while small, the proportion of patients with serious adverse events, not further defined in the article, were higher in the sofosbivir group, 3% versus 1%. Note that the above report also included what was euphemistically called a "single-group, open-label study."  This seems to be a fancy name for what is usually called a case series, that is, a series of patients given a particular treatment, without a control group.  The consensus in the evidence-based medicine community has long been that barring miraculous results, case series are nearly useless as evidence about treatments, primarily because it is not possible to separate the effects of the patient selection process from the treatment on the apparent outcomes.  Why this case series was included in the report is a secret known only to New England Journal editors. So setting aside that distraction, it is not obvious that sofosbivir increases even short-term virological response (at 12 weeks after treatment) compared to the best previously available treatment.  There is no evidence that sofosbivir can cure nearly everyone.  (Much of the enthusiasm seems to come from blood tests on treatment, disregarding the results shortly after treatment.)  These are not "spectacular" results." Sofosbuvir is extremely safe and has few side effects From the above trial results, it is not obvious that the drug is extremely safe.  In fact, there is a suggestion that it may lead to an increase in serious adverse effects. While the drug does seem to produce fewer bothersome adverse effects, even the rates of these symptoms in those treated are not negligible. Summary While there is concern about the gargantuan price asked for Sovaldi, the new treatment for hepatitis C, there seems to be little skepticism about the near miraculous claims made for the value of the new drug.  In fact, it almost appears that the debate about the price is reinforcing current dogma which promises nearly universal cures without major risks.  Yet the evidence is that many, perhaps most patients with hepatitis C will not benefit from treatment, and that the new drug is not much more, or any more likely to cure patients than older drugs.  Meanwhile, the evidence that the new drug is safer and causes fewer adverse effects is weak at best. The US health care system, and to some extent the health care systems in most developed countries are experiencing ever higher prices.  Much of these prices' effects seem to drive up remuneration of health care executives and managers, but whether they buy better care or outcomes for most people is not so clear.  The ever rising prices seem to be buoyed by endless enthusiasm for new tests, treatments, programs, and unbridled faith in the benefits of all new technology.  It is not clear how much of that is due to evidence, how much is based on ideology and unquestioning faith in technological progress, and how much is driven by marketing and public relations, which not always may be entirely honest and free from deception. Evidence-based medicine rigorously applied suggests that individual health care and health policy decisions should be driven by the best available evidence, mostly from clinical research, about the benefits and harms of tests, treatments, programs, and so on, in the context of what outcomes matter to patients.  The skepticism EBM should engender lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism. References 1.  Seeff LB, Miller RN, Rabkin CS et al.  45-year follow-up of hepatitis C virus infection in healthy young adults.  Ann Intern Med 2000; 132: 105-111.  Link <a href="http://annals.org/article.aspx?articleid=713226">here</a>. 2.  Kenny-Walsh E, for the Irish Hepatology Research Group.  Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.  N Engl J Med 1999; 340: 1228- 1233.  Link <a href="http://www.nejm.org/doi/full/10.1056/NEJM199904223401602">here</a>. 3. Seeff LB, Hollilnger B, Alter HJ et al.  Long-term mortality and morbidity of transfusion- associated non-A, non-B, and type C hepatitis: a National Heart Lung and Blood Institute Collaborative Study.  Hepatology 2001; 33: 455-463.  Link <a href="http://www.ncbi.nlm.nih.gov/pubmed/11172349">here</a>. 4. Chou R, Hartung D, Rahman B et al.  Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review.  Ann Intern Med 2013; 158: 114.-123.  Link <a href="http://annals.org/article.aspx?articleid=1402433">here</a>. 5.  Lawitz E, Mangia A, Wyles D et al.  Sofosbuvir for previously untreated chronic hepatitis C infection.  N Engl J Med 2013; 368: 1878-1887.  Link <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1214853">here</a>.

Too Good to be True - Sovaldi Kerfuffle Focuses on Price, While Ignoring Limits of Evidence about Effectiveness and Safety

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27 Mar 2014

Use of Psychological Manipulation of Physicians to Sell Pharmaceuticals: The Drug Representative as "Den Mother"

We have discussed, most recently <a href="http://hcrenewal.blogspot.com/2013/09/vested-interests-and-their-influence-on.html">here</a>, how marketers of health care goods and services use <a href="http://hcrenewal.blogspot.com/search/label/deception">deception</a> and psychological manipulation to sell their goods.  Physicians, of course, are particular targets of marketers of drugs and devices.  A vivid anecdote showing how this works just <a href="http://well.blogs.nytimes.com/2013/10/03/for-med-students-love-from-the-drug-rep/">appeared</a> on a New York Times blog.  It may be easier to recall that psychological theories: <blockquote class="tr_bq">In the social and culinary wasteland that was residency training, it had been easy for Cheryl, a bubbly brunette in her mid-30s, to become our den mother. She never tired of listening to our grousing, had unerring taste in take-out, made it a point to come to our parties when invited and every so often brought in a plate of her homemade brownies. But Cheryl was no den mother. She was a pharmaceutical rep. That she managed to slip a plug for her wares into every conversation or tuck copies of studies promoting her product into our white coat pockets as we polished off her brownies was awkward. But we always overlooked the salesmanship because it was such a familiar part of our residency routine. As trainees in a large teaching hospital, we knew numerous sales reps by name and the products they peddled; and it was odd, even disappointing, to go to an educational conference where one of them was not standing next to a table laden with tchotchkes, information brochures and free take-out.  But in retrospect, such docile acceptance was problematic. In an environment where no one, including senior doctors, ever questioned the presence of sales reps, we didn’t think too hard about why they might have been as friendly and helpful as they were. We didn’t ask where the money for all these giveaways was coming from and we were rarely curious about who these reps actually were (I only ever knew their first names). It wasn’t that I or the other residents preferentially prescribed their products. But I do know that more than once when faced with a decision about what to prescribe, the first thought that came to mind was not what I needed to do to find the latest evidence-based recommendation, but what Cheryl had just told us over lunch.  All of this became painfully clear after Cheryl suddenly disappeared. At first, the other trainees and I thought she had been fired, so we avoided bringing her absence up with the rep who replaced her. But when I ran into someone from her company at a national medical conference a year later, I learned otherwise. 'Oh, she got promoted,' the rep said, smiling broadly. 'Now she’s an executive in the central office.' </blockquote> Since Ahari and Fugh-Berman wrote and testified about the cynical tactics used in the marketing of drugs and other medical products years ago (look <a href="http://hcrenewal.blogspot.com/2007/05/fool-me-once-shame-on-you-fool-me-twice.html">here</a>, <a href="http://hcrenewal.blogspot.com/2008/03/what-drug-reps-really-care-about.html">here</a>, and <a href="http://hcrenewal.blogspot.com/2008/04/more-about-cynical-world-of-drug-reps.html">here</a>), it is now inexcusably naive for doctors to believe that drug (or device) representatives are their friends, no matter how friendly they appear.  Drug and device reps are trained to appear to be likable.  They may look like sympathetic friends, glamorous companions, or in this case, den mothers.  But as Sah and Fugh-Berman noted (look <a href="http://hcrenewal.blogspot.com/2013/09/vested-interests-and-their-influence-on.html">here</a>), likability is a ruse to sell products.  Brownies are supplied to give the appearance of warmth and comfort, and to generate feelings of reciprocity. How well it works appears above: "the first thought that came to mind was not what I needed to do to find the latest evidence-based recommendation, but what Cheryl had told us over lunch."  That it works well is demonstrated by Cheryl's promotion to an executive office. As long as physicians remain trusting, naive, or foolish in their approach to deceptive marketing, there will be more use of needlessly expensive, and sometimes needlessly toxic drugs, and more drug reps made into well-paid executives.

Use of Psychological Manipulation of Physicians to Sell Pharmaceuticals: The Drug Representative as "Den Mother"

We have discussed, most recently here, how marketers of health care goods and services use deception and psychological manipulation to sell their goods. Physicians, of course, are particular targets …

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04 Oct 2013

The Best Governance for Medicines ... is in Thailand

The Best Health Care System in the World?  Here in the US, a lot of people have been convinced that we have the best health care system in the world.  For example, during the 2012 US presidential campaign, Politi-Fact <a href="http://www.politifact.com/truth-o-meter/statements/2012/jul/05/john-boehner/john-boehner-says-us-health-care-system-best-world/">reported</a>, <blockquote class="tr_bq">House Speaker John Boehner, R-Ohio, says the health care law signed by President Barack Obama -- and upheld by the U.S. Supreme Court -- imperiled the nation’s health care system. 'Gov. Romney understands that Obamacare will bankrupt our country and ruin the best health care delivery system in the world,' Boehner said, during the July 1, 2012, edition of <a href="http://www.cbsnews.com/8301-3460_162-57464563/face-the-nation-transcripts-july-1-2012-speaker-boehner-senators-schumer-and-coburn-governors-walker-and-omalley/?pageNum=2&tag=contentMain;contentBody">CBS’ Face the Nation</a>. Boehner wasn’t the only one making that claim on the Sunday talk-show circuit. On <a href="http://www.foxnews.com/on-air/fox-news-sunday/2012/07/02/white-house-ready-move-and-implement-health-care-law-mcconnell-we-can-defeat-obamacare-no?page=4">Fox News Sunday</a>, Senate Minority Leader Mitch McConnell, R-Ky., added that the U.S. has 'the finest health care system in the world.'</blockquote> More recently, as the Huffington Post<a href="http://maddowblog.msnbc.com/_news/2013/03/25/17455963-the-greatest-health-care-system-the-world-has-ever-known?"> reported</a>, <blockquote class="tr_bq">Sen. Jeff Sessions (R-Ala.) charged Thursday that Obamacare is destroying the 'greatest health care system the world has ever known' and that it was 'horrible' for anyone to suggest Americans receive anything less than the best care, even though they die younger on average than people in many other countries. 'This is just one example of what happens in this country when people in Washington take on the arrogant view that they know how to fix the health care system -- one of the most massive, complex, marvelous systems the world has ever known,' Sessions said on the Senate floor.</blockquote> One would expect that the greatest health care system in the world would have the greatest pharmaceutical industry in the world too.  In fact, as noted by Politi-Fact,  that is pretty much what Congressman Boehner asserted, <blockquote class="tr_bq"> Boehner’s office also noted that wealthy foreigners flock to the U.S. to receive care because of its cutting-edge facilities, and that the U.S. is among the leaders, if not No. 1, in medical research and pharmaceutical development.</blockquote> Not the Best Governance for Medicines in the World A recent <a href="http://www.bernama.com.my/bernama/v7/wn/newsworld.php?id=951522">article</a> from the National News Agency of Malaysia will probably not get a lot of attention in the US, or other developed countries, but it does suggest another reason to be very skeptical about shouts of "USA Number 1" at least applied to health care.  The article's main point was: <blockquote class="tr_bq">The World Health Organisation (WHO) has praised Thailand for the world's best governance for medicine, Thai News Agency (TNA) reported. Public Health Minister Dr. Pradit Sintawanarong, who is attending the 66th World Health Assembly in Geneva, Switzerland, from May 20-28, told journalists on Wednesday that the WHO has asked Thailand to co-organise a meeting on good governance for medicine, as the Thai Kingdom is considered the world's most advance in governance for medicine and should be a good example for other countries. Dr. Pradit, who was invited by the WHO to open a meeting on Thailand's governance for medicine and health systems, held as part of the 66th World Health Assembly, acknowledged that the WHO has also asked Thailand to share experiences in another side meeting on 'Good Governance in the Pharmaceutical Sector:The Case of Thailand and Malawi'.</blockquote> Again, a lot of people think of the US health care system as a model of the rest of the world.  Here is one little bit of data that maybe it should not be the model for "governance for medicine."  Of course, that phrase itself is almost never used here.  Its definition, however, should be instructive. The World Health Organization has had a small "Good Governance for Medicines" program since 2004.  We first discussed it <a href="http://hcrenewal.blogspot.com/2008/12/two-important-resources.html">here</a> in 2008  On the <a href="http://www.who.int/medicines/ggm/en/">program web-site</a>, its goal is defined: <blockquote class="tr_bq">contributing to health systems strengthening and preventing corruption by promoting good governance in the pharmaceutical sector. Specifically the programme aims: -To raise awareness on the impact of corruption in the pharmaceutical sector and bring this to the national health policy agenda - To increase transparency and accountability in medicine regulatory and supply management systems - To promote individual and institutional integrity in the pharmaceutical sector - To institutionalize good governance in pharmaceutical systems by building national capacity and leadership. </blockquote> So if Thailand received recognition for having the best governance for medicines, the implication is that the US does not. In fact, we and other dissidents have documented a host of problems with individual and institutional integrity in the pharmaceutical sector, lack of transparency and accountability in medicine regulatory and supply management systems, and actual corruption in the pharmaceutical sector.  Some of the most recent big examples on Health Care Renewal since December, 2012, include: -  the CEO of drug and biotechnology company Amgen collected tens of millions of dollars while his company settled lawsuits alleging it gave kickbacks to doctors, pharmacists and others to use potentially dangerous medicines (post <a href="http://hcrenewal.blogspot.com/2013/05/amgen-ceos-prosper-despite-or-because.html">here</a>) -  Pfizer's 14 legal settlements since 2000, including settlements of allegations of fraud, illegal promotion of hazardous drugs, kickbacks given to physicians, bribery of foreign officials, etc.  The biggest was for $2.3 billion.  In one case, the company was convicted of being a racketeering influenced corrupt organization (RICO) (post <a href="http://hcrenewal.blogspot.com/2013/01/pfizers-pfourteenth-settlement-small.html">here</a>). - Three settlements in the US by GlaxoSmithKline in 2012, of allegations including deceptive marketing to hide drugs' adverse effects, improperly preventing generic competition, and a $3 billion settlement for deceptive marketing and improper promotion of multiple drugs (post <a href="http://hcrenewal.blogspot.com/2012/12/tis-season-for-legal-settlements.html">here</a>). - Eli Lilly settled allegations that it bribed foreign officials.  (In 2009 it pleaded guilty to criminal charges arising from deceptive marketing of Zyprexa) (post <a href="http://hcrenewal.blogspot.com/2012/12/tis-season-for-legal-settlements.html">here</a>) - After making two settlements of overcharging the US government in 2007 and 2009, Sanofi settled US allegations of giving kickbacks to doctors (post <a href="http://hcrenewal.blogspot.com/2012/12/tis-season-for-legal-settlements.html">here</a>).. -  The pharmaceutical paid "key opinion leader" who was most influential in promoting widespread use, and probably overuse of opiates, admitted it was all "misinformation" (post <a href="http://hcrenewal.blogspot.com/2012/12/the-king-of-pain-recants-pharmaceutical.html">here</a>). See also our posts on <a href="http://hcrenewal.blogspot.com/search/label/bribery">bribery</a>, <a href="http://hcrenewal.blogspot.com/search/label/kickbacks">kickbacks</a>, <a href="http://hcrenewal.blogspot.com/search/label/fraud">fraud</a>, <a href="http://hcrenewal.blogspot.com/search/label/crime">crime</a>, and <a href="http://hcrenewal.blogspot.com/search/label/health%20care%20corruption">corruption</a>, not to mention <a href="http://hcrenewal.blogspot.com/search/label/deception">deception</a>, <a href="http://hcrenewal.blogspot.com/search/label/stealth%20marketing">stealth marketing</a>, <a href="http://hcrenewal.blogspot.com/search/label/conflicts%20of%20interest">conflicts of interest</a>, <a href="http://hcrenewal.blogspot.com/search/label/institutional%20conflicts%20of%20interest">institutional conflicts of interest</a>, etc. Participatory Democracy in Health Care So good for the Thais for apparently doing much better with far fewer resources.  One reason seems to be that the government has made good governance for medicines, defined as above, a big priority: <blockquote class="tr_bq">According to the public health minister, the Thai government and his ministry have adhered great importance to good governance for medicine (GGM) and health systems and Thailand has also joined the WHO's campaigns on the GGM from the first stage, concerning the assessment of the situation and the installation of relevant systems.</blockquote> I can also speculate that one reason they have done better is their conscious effort to enlist the public at large in discussing and setting the direction of their health care system.  For example, as we <a href="http://hcrenewal.blogspot.com/2009/09/making-health-care-more-representative.html">discussed</a> in 2009,  Thailand has set up by law a National Health Assembly, with its <a href="http://en.nationalhealth.or.th/Health_Assembly">stated goal</a> to be: <blockquote class="tr_bq">an instrument as well as a learning process to develop participatory public polices on health and pushing for practicability.</blockquote> Assemblies have been held yearly since 2008.  A detailed report on the 2008 assembly is <a href="http://www.who.int/sdhconference/resources/rasanathan_healthexpectations.pdf">here</a>. [Rasanathan K, Posayanonda T, Birminghan M et al.  Innovation and participation in the first National Health Assembly in Thailand. Health Expectations 2012; 15: 87-96].  The most recent was in December, 2012 (look <a href="http://en.nationalhealth.or.th/nha2012">here</a>.)   Such a mechanism for broad public input into health care does not obviously occur in the US.  Instead, we have corporations spending billions on <a href="http://hcrenewal.blogspot.com/search/label/stealth%20lobbying">lobbying</a>, <a href="http://hcrenewal.blogspot.com/search/label/public%20relations">public relations</a>, <a href="http://hcrenewal.blogspot.com/search/label/stealth%20health%20policy%20advocacy">stealth advocacy</a>, and campaign contributions.  We have the constant interchange of top government and corporate health care leaders via the <a href="http://hcrenewal.blogspot.com/search/label/revolving%20doors">revolving door</a>. We do not have any significant public discussion of good governance for medicines, or anything like it.  (The few, rare exceptions about which I know are the recent Healthy Skepticism meeting on <a href="http://sellingsickness.com/">Selling Sickness</a>, and the now yearly meetings organized by <a href="http://pharmedout.org/">PharmedOut.org</a>)  Discussion of deception, conflicts of interest, crime and corruption affecting large health care organizations is muted and <a href="http://hcrenewal.blogspot.com/search/label/anechoic%20effect">anechoic</a>.  I know of precisely one course on health care corruption in any US medical, public health, or health administration school (look<a href="http://hcrenewal.blogspot.com/2009/12/how-to-give-course-on-corruption-in.html"> here</a>, and its focus is on developing countries.) Time to head to Bangkok?....  But if we all cannot...  In the US, we will not have a chance of meaningfully improving our health care system until we start listening to unbiased health care professionals and academics (in particular, who have not been paid off by vested interests),  civil society organizations, and people and patients at large, and stop getting all our insight from corporate executives, their cronies, and their paid experts.  We will not have a chance until we allow discussion of all the problems, including bad leadership and governance, dishonest and deceptive practices, conflicts of interests, and outright crime and corruption.  We will not have a chance until we put our priority on patients' and the public's health, not the vested interests of those who have gotten rich off the current dysfunctional system.  .

The Best Governance for Medicines ... is in Thailand

The Best Health Care System in the World? Here in the US, a lot of people have been convinced that we have the best health care system in the world. For example, during the 2012 US presidential camp…

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23 May 2013

Doctors' Dubious Excuses for Taking Pharmaceutical Companies' Money

Pro Publica has updated their database of payments by pharmaceutical payments to physicians and organizations.  It now has data from 15 companies totaling more than $2 billion from 2009 to 2012. To accompany <a href="http://www.propublica.org/article/dollars-for-docs-mints-a-millionaire">Pro Publica's report</a>, a number of news outlets wrote about payments given to local or regional doctors.  These included, in semi-random order, the Los Angeles Daily News (<a href="http://www.dailybulletin.com/breakingnews/ci_22751458/california-doctors-report-prescription-drug-company-payments-speaking-engagements">via the Inland Valley Daily Bulletin</a>), the <a href="http://www.sltrib.com/sltrib/news/55962410-78/drug-research-drugs-industry.html.csp">Salt Lake (City, Utah) Tribune</a>, the <a href="http://www.mercurynews.com/breaking-news/ci_22776326/drug-companies-pay-millions-california-doctors-speaking-meals">San Jose (California) Mercury News</a>, <a href="http://www.newschannel5.com/story/21592977/nashville-psychiatrist-paid-more-than-1m-by-drug-companies">NewsChannel5</a> in Nashville, Tennessee, the <a href="http://www.pasadenastarnews.com/news/ci_22769057/city-hope-area-doctors-receive-funding-from-drug">Pasadena (California) Star-News</a>, the Bergen and Passaic, New Jersey Record Herald via<a href="http://www.northjersey.com/news/Drug_firms_paid_2B_to_doctors_to_pitch_products_and_conduct_research_study_says.html"> NorthJersey</a>, the <a href="http://articles.philly.com/2013-03-14/news/37654205_1_joseph-pharmaceutical-giants-foot-doctor">Philadelphia Inquirer</a>, and the <a href="http://www.dispatch.com/content/stories/local/2013/03/17/prescription-for-conflict.html">Columbus (Ohio) Dispatch</a>. The combined reports showed that many physicians, including prominent academics and community practitioners, are still getting a lot of money from pharmaceutical firms.  Since Pro Publica was only able to get data from some US drug companies, albeit those who accounted for 47 percent of US drug sales, it is likely that many more doctors than those in the data base got such payments, and the doctors in the data base may have gotten more money from companies that do not report their payments.  In addition, it is likely that many more doctors get similar payments from medical device companies, health care information technology companies, and other for-profit corporations that promote health care products and services.   We had discussed Pro Publica's initial reporting from its database <a href="http://hcrenewal.blogspot.com/2010/10/not-best-and-brightest-drug-marketers.html">here</a>.  While there is evidence that most payments to doctors by pharmaceutical companies are intended to promote marketing, we discussed <a href="http://hcrenewal.blogspot.com/2010/11/of-drug-talks-deception-and-denial.html">here</a> how some doctors rationalized their payments as fully professional and proper. Now the updated reporting has provided many examples of - not to put too fine a point on it - physicians making dubious excuses for their acceptance of payments, often large, from pharmaceutical companies. Their themes included It's Education, What Could Possibly Go Wrong? From Pro Publica, <blockquote class="tr_bq">[Dr Rakesh] Jain, of Lake Jackson, Texas, has earned $582,049.  [Dr Vladimir] Maletic, of Greer, SC, made $527,850<a href="http://projects.propublica.org/docdollars/search?utf8=%E2%9C%93&term=Vladimir+Maletic&state%5Bid%5D=&services%5B%5D=&period%5B%5D=">,</a> according to Dollars for Docs.</blockquote> So, <blockquote class="tr_bq">Jain said he loves teaching and delivers the same lectures about drugs and medical conditions regardless of whether a drug company is paying him. 'I am not a marketer, I am an educator,' Jain said.</blockquote> Also <blockquote class="tr_bq">Maletic said he speaks about treatments for mood disorders, schizophrenia and sleep-wakefulness disorders because he believes that 'good quality education about pharmaceutical products may be beneficial to both physicians and their patients.'</blockquote> The LA Times found someone with a similar opinion. <blockquote class="tr_bq">'Pharmaceutical companies used to take doctors to dinner, but that was banned years ago,' said Dr. Arthur Chanzel Jeng, an infection control specialist at UCLA-Olive View Medical Center in Sylmar.  'Now they must provide some educational content.' Jeng was paid $80,500 by Pfizer last year for several speaking engagements. As an infection control specialist at Olive View, he and others in his field are concerned about drug resistant diseases and the limited number of antibiotics. Drug companies have little incentive to produce new antibiotics, he said, so if they do, physicians in his field want to know more about the drugs. That's why he agrees to speak. 'We (speakers) provide education when a new antibiotic does get released,' he said. 'There needs to be education among doctors on how to use this new antibiotic.'</blockquote> In addition, the Salt Lake Tribune noted that  <blockquote class="tr_bq"><div class="TEXT_w_Indent">[Dr Eliot] Brinton received two of the single largest payments in Utah, both in excess of $85,000, for promoting drugs by GlaxoSmithKline, ProPublica’s database shows. He describes the lectures as educational and based on science.</div><div class="TEXT_w_Indent"> </div><div class="TEXT_w_Indent">'I love the science and I love to teach. And doctors are glad to better understand the drugs and how to use them. I’m careful not to act as a cheerleader,' he said. 'If I’m a shill for the drug company I lose my integrity and integrity is really all I have to offer my patients and the drug companies.'</div></blockquote> The physicians above all asserted that since their activities were "educational," they must be worthwhile. Note that the ostensibly educational activities described above all appear to be "drug talks," that is talks sponsored by the drug companies, probably through speakers' bureaus, and given probably not as part of formal, accredited continuing medical education.  Since the publication of "Dr Drug Rep" in the New York Times in 2007, the public has learned that such talks mainly include content provided by the pharmaceutical companies, and are meant by the companies as marketing exercises.  From that case we also learned that physicians who deviate from the marketing message do not last long on speakers' bureaus.  (See posts <a href="http://hcrenewal.blogspot.com/2007/11/is-it-medical-education-or-is-it.html">here</a> and <a href="http://hcrenewal.blogspot.com/2007/11/most-popular-dr-drug-rep.html">here</a>.)  In addition, pharmaceutical companies often pay physicians deemed to be "<a href="http://hcrenewal.blogspot.com/search/label/key%20opinion%20leaders">key opinion leaders,</a>" whose opinions are promoted supposedly for their brilliance and erudition.  However, as noted <a href="http://hcrenewal.blogspot.com/2008/06/key-opinion-leaders-were-sales-people.html">here</a> and <a href="http://hcrenewal.blogspot.com/2010/10/not-best-and-brightest-drug-marketers.html">here</a>, the companies buying their services believe they have bought the services of sales people.    Evidence about key opinion leaders actually performing like marketers has come from documents revealed during litigation (e.g., see this <a href="http://hcrenewal.blogspot.com/2012/07/giant-gsk-settlement-provides-reminder.html">recent example</a> of a huge monetary settlement made of charges that GlaxoSmithKline, a major multinational drug company committed fraud among other things, and in the course of its unethical activities used key opinion leaders as marketers).   Also, see the Neurontin marketing plan (see post <a href="http://hcrenewal.blogspot.com/2006/08/stealth-marketing-of-neurontin.html">here</a>), and the Lexapro marketing plan (see post <a href="http://hcrenewal.blogspot.com/2009/09/lexapro-marketing-plan-was-meant-to.html">here</a>) for examples of how company keaders view key opinion leaders as marketers. Given the volume of evidence about drug talks, speakers' bureaus, and the marketing purposes of key opinion leaders, the assertion that because they were in some sense educational, these doctors' corporate financed talks were worthwhile is at best a silly excuse. More formally, it may arise from a logical fallacy.  The doctors appeared to be arguing that education is an unalloyed good.  However, obviously not all education is good education, or unbiased education. Specifically in this case, logic, and evidence from several cases in which pharmaceutical companies' intentions as documented in communications revealed in litigation (see examples <a href="http://hcrenewal.blogspot.com/search/label/stealth%20marketing">here</a>) suggest that these companies pay physicians for education that they believe serves marketing purposes.Thus the doctors seem to be using the <a href="http://www.nizkor.org/features/fallacies/composition.html">composition fallacy</a>, the logical fallacy that an entire class (in this case, all of education) can be judged by some of its members (examples of unbiased, accurate, good education.)  <div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">It's Research, What Could Possibly Go Wrong?  </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"></div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">Similarly, the doctors who get paid to do research say it's all about the research.  The Salt Lake Tribune reported on</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"></div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"><blockquote class="tr_bq"><div class="TEXT_w_Indent">CRI LifeTree Research, which has received at least $3.4 million in drug company payments since 2009, according to ProPublica. </div><div class="TEXT_w_Indent"> </div><div class="TEXT_w_Indent">Co-founder <a href="http://www.crilifetree.com/lynnwebster" target="_blank">Lynn Webster</a>, an anesthesiologist, is listed as having received the single largest payment in the state: $1,687,771 from Cephalon, a big maker of pain medications. Only three other doctors in the country received more from Cephalon. </div><div class="TEXT_w_Indent"> </div><div class="TEXT_w_Indent">Nationally, Webster is among the top 50 for single largest payments received, behind marquee hospitals, such as the Mayo Clinic, Cleveland Clinic and Duke and Harvard Universities.</div><div class="TEXT_w_Indent"> </div><div class="TEXT_w_Indent">A nationally recognized expert in pain management, Webster <a href="http://www.sltrib.com/sltrib/news/55905155-78/pain-webster-patients-deaths.html.csp" target="_blank">is under investigation</a> by the U.S. Drug Enforcement Administration, which is looking into opioid overdose deaths of patients of his former pain clinic. A Senate Committee is probing his financial ties to Big Pharma.</div></blockquote><div class="TEXT_w_Indent"> </div><div class="TEXT_w_Indent">Webster insisted,</div><div class="TEXT_w_Indent"> </div><blockquote class="tr_bq"><div class="TEXT_w_Indent">Research payments to him cover overhead and other costs, including his salary as a lead researcher, he said. </div><div class="TEXT_w_Indent"> </div><div class="TEXT_w_Indent">'Research inevitably leads to better education, better systems and better therapies — things that are indispensable for medical advancement and quality care,' he said. </div></blockquote><div class="TEXT_w_Indent"> </div><div class="TEXT_w_Indent">The Pasadena Star-News provided this version,</div><div class="TEXT_w_Indent"> </div><blockquote class="tr_bq"><div class="TEXT_w_Indent"></div>Pasadena-based plastic surgeon John Edward Gross received more than $770,000 from Allergan, the maker of Botox and some breast implants. In 2011-12, Allergan paid Gross to conduct research, consult, serve on health care panels and business travel. 'What I'm doing for Allergan is to advance breast surgery,' said Gross, a board certified surgeon and a former chemical engineer. 'Much of the research you do is industry-supported. They have a motivation to make better and new products.' </blockquote><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">It is pretty amazing to see the notion that all clinical research is irreproachable in print.  We and others have documented huge numbers of cases and volumes of evidence that clinical research may be <a href="http://hcrenewal.blogspot.com/search/label/manipulating%20clinical%20research">manipulated</a>, and, if necessary, <a href="http://hcrenewal.blogspot.com/search/label/suppression%20of%20medical%20research">suppressed</a> to support the commercial goals of those who make products or provide services assessed by such research.  In fact, the prestigious Institute of Medicine's <a href="http://www.iom.edu/Reports/2009/Conflict-of-Interest-in-Medical-Research-Education-and-Practice.aspx">report </a>on Conflict of Interest in Medical Research, Education and Practice included the recommendation (4.1) that "individuals may not conduct research with human participants if they have significant financial interest in an existing or potential product or a company that could be affected by the outcome of research."  Given the volume of this evidence, the assertion that all pharmaceutical company clinical research should be irreproachable is just plain silly. Again, formally the physicians' arguments, if they should be dignified with that name, seem to arise from the same logical fallacy discussed above.  The underlying argument seems similar to that made above about education: "I am doing research.  All research is good, unbiased, helpful to patients.  So what I am doing is good, unbiased, helpful research."  So it appears the composition fallacy again was in play.</div><div class="TEXT_w_Indent"> </div></div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"></div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">It's Not Really My Money</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">The San Jose Mercury News provided this example,</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><blockquote class="tr_bq"><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">The database links Dr. Gurkirpal Singh to more than $248,000 in Pfizer payments it lists for speaking, consulting, travel and meals since 2009. He said all the money went to Institute of Clinical Outcomes Research and Education in Palo Alto, where he is the chief scientific officer. Singh said the money paid for research. </div></blockquote><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"><blockquote>'I receive nothing -- let me be very clear on that,' said Singh, who is an adjunct clinical professor at Stanford University.</blockquote> The Columbus Dispatch added, <blockquote class="tr_bq"> Dr. Henry Nasrallah, a psychiatrist at the University of Cincinnati, netted $647,341 in speaking and consulting fees from drug companies, ranking him as Ohio’s top recipient of such payments over that four-year period. Cincinnati’s College of Medicine put that money toward his $222,232 annual salary. 'The (pharmaceutical) companies have a signed agreement with the university for my activities, not with me personally,' Nasrallah wrote in an email to The Dispatch. 'This is another reason why I maintain scientific and clinical impartiality about the various drugs I teach, because I do not have a direct personal gain,' wrote Nasrallah, a former chairman of Ohio State University’s psychiatry department.</blockquote></div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">Really, the boss doesn't care whether he brings in any money? </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"></div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">These doctors seem to be denying that money is fungible.  In other words, they seem to be arguing that money going to the organizations that pays them is different from money going directly to them, and that their bosses do not in fact care whether their activities bring any revenues to the organization.  This just flies in the face of common sense. </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">Someone Needs to Pay</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">NewsChannel5 was able to interview the top earner on the Pro Publica list, Dr Jon W Draud, who said among other things,  </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> </div><blockquote class="tr_bq"><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">it was only fair to accept payments for his speaking engagements because it makes up for what he would otherwise make while working at his practice.</div></blockquote><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"><blockquote> 'It's not essential, I suppose, but I consider it a reasonable, fair compensation for being gone and traveling, and spending time away from my home and family,' Draud said.</blockquote>If Dr Draud was providing education, a useful service, it seems reasonable that someone should pay for it.  However, he appears to <a href="http://www.nizkor.org/features/fallacies/begging-the-question.html">beg the question</a> of who should pay for it?  Underlying this question is the concern that since it was pharmaceutical companies, not students, who were paying, the education was being done primarily to benefit the former, through marketing, rather than the latter.  The apparent argument, that because it is not reasonable to get paid for services, any source of payment is acceptable, is again just plain silly.  Who Cares About Money? NewsChannel5 also reported that Dr Draud said <blockquote class="tr_bq"> accepting so much money did not create a conflict of interest between him and his patients. He said the information he gives out was not biased towards the drug companies.</blockquote> However, the Institute of Medicine<a href="http://www.iom.edu/Reports/2009/Conflict-of-Interest-in-Medical-Research-Education-and-Practice.aspx"> report </a>on Conflict of Interest in Medical Research, Education and Practice defined conflict of interest as "circumstances that create a risk that professional judgments or actions regarding a primary interest will be unduly influenced by a secondary interest."  Asserting that receiving over $1 million could not create even a risk that his educational presentations were biased towards the interests of those who gave him that money seems like simple denial.   The FDA Said it Was True Top earner Dr Draud also said according to NewsChannel5, <blockquote class="tr_bq"> It has to be vetted by the FDA as being fair, balanced and non-biased toward the pharmaceutical company....</blockquote> From the Philadelphia Inquirer, re Dr Warren S Joseph, a podiatrist who received over $650,000 <blockquote class="tr_bq">Joseph acknowledged the payments in an email to Philly.com. 'All of my lectures given for the Pharma industry follow strict FDA guidelines and are consistent with the corporate integrity agreements entered into between the companies and the government,' Joseph said. 'There is full disclosure of this fact at all lectures.'</blockquote> These justifications appear to be just plain wrong.  As far as I know, the US Food and Drug Administration does not pre-approve "drug talks" given by physicians for pharmaceutical companies. By the way, the statement by Dr Joseph approaches self parody.  As we have discussed, <a href="http://hcrenewal.blogspot.com/search/label/corporate%20integrity%20agreements">corporate integrity agreements</a> are usually the products of legal settlements of charges of wrongdoing.  Drug companies do not sign such agreements because of previous good behavior.  Moreover, I have never heard of such an agreement that required pre-approval of drug talks, either.   Trust Me, I'm an Expert  As reported by NorthJersey, <blockquote class="tr_bq">One of the top recipients in North Jersey was Thomas Dayspring, an internist and expert in cholesterol management, who earned just under $400,000 from Merck and GlaxoSmithKline. Dayspring said he was paid for lectures at conferences for doctors arranged by the drug companies, as well as continuing medical education programs. 'I’ve logged over 2 million miles, all over the world and in all 50 states,' said Dayspring, who served as the director of the North Jersey Institute of Menopausal Lipidology in Wayne until last summer. 'Guys like me who are nationally known attract a big audience. Not every speaker can trot out a CV like mine.'</blockquote>New Jersey, you gotta love it.  The most charitable characterization of this is an <a href="http://www.nizkor.org/features/fallacies/appeal-to-authority.html">appeal to authority</a>, albeit an amazingly egotistical one.  Summary  Two years after Pro Publica's report, pharmaceutical companies are continuing to pay substantial sums to physicians and other health professionals, nominally for education and research.  Because these arrangements are financially beneficial to the professional recipients of the money, and likely financially beneficial via their marketing effects  to the companies that provide the money , it should be no surprise that they are continuing in the absence of any regulatory restrictions. What is saddest about the latest reporting is the silliness of the excuses made by the conflicted physicians.  Professionals with four years of education post-college, and multiple years of experience, and who are often respected as academics or practitioners ought to be able to reason and argue better than they did in the examples above.  Of course, people who make a lot of money often come to believe they really deserve it.  And conflicts of interest produce conflicted thinking.  As Joe Collier wrote in the BMJ, " people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult." (Look<a href="http://hcrenewal.blogspot.com/2006/06/british-medical-journal-highlights.html"> here</a>.) The IOM  <a href="http://www.iom.edu/Reports/2009/Conflict-of-Interest-in-Medical-Research-Education-and-Practice.aspx">report </a> on conflicts of interest suggested full disclosure of all payments that could be considered conflicts of interest, banning clinical research by conflicted individuals, prohibiting academic physicians from giving "drug talks" whose content was provided by industry, and developing methods to fund continuing medical education independent from industry.  This report, and its recommendations have gotten scant attention, maybe because they would threaten a status quo that enriches conflicted health professionals and the companies that create these conflicts.  However, in my humble opinion, implementing all the report's recommendations would only be a beginning down the road of restoring the integrity of clinical care, teaching, and research.   </div>

Doctors' Dubious Excuses for Taking Pharmaceutical Companies' Money

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19 Mar 2013

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