healthy4u: manipulating clinical research

What Does the Blumsohn - Procter and Gamble -Sheffield University Affair Say About the Fitness of the Latest VA Secretary Candidate?

Introduction - New Leadership for the US Department of Veterans Affairs After reports of problems with access, manipulation of data about waiting times, and most recently "a corrosive culture," the US Department of Veterans Affairs, the country's large government run health system, has had a massive leadership overhaul.  President Obama's nominee to head the agency is now Robert A McDonald, former CEO of Procter and Gamble. The choice of a former CEO or a large corporation was called "unorthodox" <a href="http://www.bostonglobe.com/news/nation/2014/06/29/bob-mcdonald-former-chief-obama-nominee-lead-veterans-affairs/zVA9EH7PlMNWaTU7Yyp8NP/story.html">by the Boston Globe</a>, but many saw merit in a business leader running the VA.  As reported by the Globe, House Speaker John Boehner said that as a "private sector" leader,  Mr McDonald is the "kind of person who is capable of implementing the kind of dramatic systemic change that is badly needed and long overdue at the VA."  The Chairman of Boeing, also a member of the P&G board, hailed Mr McDonald as the person who "navigated Procter & Gamble through the difficult post-financial-crisis years, where he expanded business in developing markets and made substantial progress improving the efficiency of the company’s internal operations...." On the other hand, a <a href="http://www.washingtonpost.com/politics/federal_government/obamas-choice-for-va-will-find-fixing-it-is-harder-than-selling-soap/2014/07/01/84cf28d6-0139-11e4-b8ff-89afd3fad6bd_story.html">column in the Washington Post</a> suggested that expertise in "selling Tide and Pantene" might not be relevant to fixing the VA. Yet aside from a <a href="http://ringoffireradio.com/2014/07/obama-nominates-former-corporate-exec-as-veteran-affairs-secretary-2/">single article</a> on the Ring of Fire web site, all news coverage and discussion so far has ignored Mr McDonald previous experience in health care leadership, but also that his relevant track record ought to raise questions about his fitness for the VA position. Procter and Gamble and Health Care According to Mr McDonald's <a href="http://www.pg.com/en_US/downloads/company/executive_team/bios/pg_executive_bio_bob_mcdonald.pdf">official P&G biograpy</a>, after various roles in various countries, before becoming CEO,  <blockquote class="tr_bq">Bob returned to the U.S. as the Vice Chairman of Global Operations (2004 to 2007) and later P&G’s Chief Operating Officer (2007 to 2009).</blockquote> Although not widely known as a pharmaceutical company, P&G actually had a subsidiary that made prescription drugs, which Mr McDonald sold off in 2009 (see this <a href="http://online.wsj.com/news/articles/SB125111032092353427">Wall Street Journal report</a>.)  As we noted <a href="http://hcrenewal.blogspot.com/2014/05/abort-retry-fail-lancet-avoided-much.html">here</a>, its products still include over the counter pharmaceuticals (e.g., Pepto-Bismal, Metamucil, Prilosec OTC).  Also, while Procter & Gamble does not make it very obvious, it has owned MDVIP, a company that employs physicians to provide concierge medical services, since 2010, although as Cincinnati.com just <a href="http://www.cincinnati.com/story/money/business/2014/05/02/pg-sells-concierge-medicine-unit/8622903/">reported</a>, it will soon sell this unit to private equity.  So during Mr McDonald's tenure, his company was to some extent a pharmaceutical company, and a health care provider. The Blumsohn - Procter and Gamble - Sheffield University Case Furthermore, on Mr McDonald's watch as Vice Chairman of Global operations and Chief Operating Officer, there was a case involving Procter and Gamble that raised multiple concerns about the ethics of its pharmaceuticals operations.  We first posted about the case in 2005 (<a href="http://hcrenewal.blogspot.com/2005/12/another-challenge-to-integrity-of.html">here</a>).  For all relevant posts, look <a href="http://hcrenewal.blogspot.com/search/label/Actonel">here</a>. In 2009 we <a href="http://hcrenewal.blogspot.com/2009/12/british-medical-journal-interviews-dr.html">described the case</a> thus, <blockquote class="tr_bq">The case involved suppression and manipulation of research, ghost-writing, institutional conflicts of interest, and attempts to silence a whistle blower. It provides lessons about the downsides of letting commercial firms sponsor and hence control human research designed to evaluate the products or services they sell; and of academic medicine becoming dependent on research money from such firms for such research.</blockquote> We previously <a href="http://hcrenewal.blogspot.com/2009/09/reappearance-of-ghost-of-seasons-past.html">summarized</a> the case's events <blockquote><ul><li>Dr Aubrey Blumsohn, a senior lecturer at Sheffield University, and Professor Richard Eastell performed a research project on the effects of the drug risedronate (<a href="http://www.actonel.com/index.jsp">Actonel</a>, made by Procter & Gamble Pharmaceuticals [P&G]) under a <a href="http://www.fraudinscience.org/PG/contract.pdf">contract</a> between P&G and the University.</li><li>Although the research contract designated Blumsohn and Eastell as "Investigators" under whose direction the project would be carried out, Blumsohn was not given access to the original data collected by the project.</li><li>Despite numerous requests, (like <a href="http://www.fraudinscience.org/PG/20050525mckay.pdf">this one</a>), P&G <a href="http://www.fraudinscience.org/PG/20030619email.htm">refused access </a>to this data <a href="http://www.fraudinscience.org/PG/attorneyreq.pdf">repeatedly</a>. Blumsohn was concerned that he and Eastell could be accused of scientific fraud if they continued to make presentations and write articles and abstracts without access to the data which they were supposedly writing about.</li><li>Blumsohn became suspicious that some of the analyses done by P&G could be misleading, especially <a href="http://www.fraudinscience.org/PG/20030909audio.htm">related to a graph shown to him that omitted 40% of patient data</a>.</li><li>Blumsohn objected to <a href="http://www.fraudinscience.org/PG/20030424email.htm">P&G arranging for papers and abstracts to be written by a professional writer</a>, but with Blumsohn listed as first author. Blumsohn was concerned that such ghost-written documents were mainly meant to convey "key messages" in support of P&G's commercial interests.</li><li><a href="http://www.fraudinscience.org/PG/20030910audio.htm">Eastell warned Blumsohn </a>not to aggravate P&G, because the company was providing a grant to the University which "is a good source of income."</li><li>After repeated failed attempt to get the data, Blumsohn complained to numerous officials at Sheffield University, including <a href="http://www.fraudinscience.org/PG/20040526eastell.pdf">Eastell</a>, medical school Dean <a href="http://www.fraudinscience.org/PG/20050708weetman.pdf">Tony Weetman</a>, University Vice-Chancellor <a href="http://www.fraudinscience.org/PG/20050814bouche.pdf">Robert Boucher</a>, and the Head of the University's Department of Human Resources, <a href="http://www.fraudinscience.org/PG/20050627boucha.pdf">Ms R Valerio</a>.</li><li>Still unable to get the data, he spoke with news reporters about his case. At this point, Sheffield suspended him, but then <a href="http://www.fraudinscience.org/PG/gag.doc">offered him a severance agreement </a>if he signed a contract binding him not to make any detrimental or derogatory statements about the University and its leaders.</li></ul></blockquote><blockquote>So the case involved suppression and manipulation of research, ghost-writing, institutional conflicts of interest, and attempts to silence a whistle blower. It provides lessons about the downsides of letting commercial firms sponsor and hence control human research designed to evaluate the products or services they sell; and of academic medicine becoming dependent on research money from such firms for such research.</blockquote> Although this case occurred in the UK, it involved actions by the US based Procter and Gamble.  While many of the events in the case occurred before 2004, from 2004 to 2009 it became clear that Procter and Gamble was not going to go easy on Dr Blumsohn.  For example, <a href="http://scientific-misconduct.blogspot.com/2007/03/advice-to-p-pharmaceuticals-how-not-to.html">according to Dr Blumsohn</a>, in 2006, P&G released some scientific data relevant to the case, but not complete enough data to be meaningful.  In 2007, there was still shady business going on involving scientific abstract submissions apparently made in Dr Blumsohn's name by P&G operatives. Since Procter and Gamble never made any known attempt to apologize, explain its conduct, or ameliorate Dr Blumsohn's plight during 2004 - 2009, as one of the most senior leaders of Procter and Gamble, seemingly with direct authority over its pharmaceutical operations in the UK during that time period, Mr McDonald ought to be held accountable for the company's misbehavior described above.  To my knowledge, though, no one at P&G, including Mr McDonald, has ever admitted responsibility or been made accountable in any way.   Summary Since Mr McDonald recently was an executive of a company that sold prescription and non-prescription pharmaceuticals, and provided direct health care, confirmation as Veterans Affairs secretary could be regarded as a transit through the revolving door, and hence open to question.  Since Mr McDonald got $15,928,015 in total compensation during his last year as CEO (2012-13) (see the company's 2013 proxy statement), and had accumulated 2,247,593 shares of stock or equivalent by 2013, worth approximately $179 million at today's price of $79.67, his ability to understand the needs of the often poor veterans whom the VA serves is also open to question.  More importantly, while Mr McDonald held high executive positions at Procter and Gamble, the company was involved in a dodgy affair involving conflicts of interest, manipulation of research, and attempted silencing of whistle blowers.  In my humble opinion, given that these events occurred directly on his watch, his fitness to run a huge health care system ought to be in question unless his responsibility for these events is disproved. The widespread huzzahs for Mr McDonald as potential VA leader based mainly on his exalted status as CEO of a big corporation show that many in the US still see corporate CEOs as aristocracy.  True health care reform would hold health care leaders accountable, particularly for upholding the health care mission and putting patients' and the public's health ahead of revenue generation and especially personal profit. ADDENDUM (7 July, 2014) - Link to McDonald's official P&G biography fixed.  ADDENDUM (8 July, 2014) - This post has been re-posted <a href="http://www.nakedcapitalism.com/2014/07/obama-va-robert-macdonald-procter-gamble-scandal.html">on Naked Capitalism</a>, and <a href="http://www.openhealthnews.com/story/2014-07-07/robert-mcdonald-fit-be-va-secretary">on Open Health News</a>.

What Does the Blumsohn - Procter and Gamble -Sheffield University Affair Say About the Fitness of the Latest VA Secretary Candidate?

Introduction - New Leadership for the US Department of Veterans Affairs After reports of problems with access, manipulation of data about waiting times, and most recently "a corrosive culture," the US…

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02 Jul 2014

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

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

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

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24 Jun 2014

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

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

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

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

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20 Jun 2014

Fool Me Twice? - Boehringer Ingelheim, Medtronic Settle Lawsuits Alleging Deceptive Marketing

It seems like it has been really quiet on the legal settlement front in the US, but maybe corporate executives wanted to wait until things calmed down after the unofficial start of summer to let out news that some people might not think reflected well on them.  So this week it was time to announce two new legal settlements of allegations of bad behavior by corporate health were announced, as we will list in alphabetical order.... Boehringer Ingelheim Settles Suits Alleging it Hid Data About Pradaxa Harms As <a href="http://www.bloomberg.com/news/2014-05-28/boehringer-pays-650-million-to-end-blood-thinner-cases.html">per Bloomberg</a>, <blockquote class="tr_bq">Boehringer Ingelheim GmbH, the German family-owned drugmaker, agreed to pay $650 million to settle the majority of lawsuits filed over its blood thinner Pradaxa, which has been linked to more than 500 patient deaths.</blockquote> The major allegations were about deception, <blockquote class="tr_bq"> Patients and their families alleged Boehringer executives knew Pradaxa posed a deadly risk to some consumers when they brought it to the U.S. market in October 2010.</blockquote> In particular, as we <a href="http://hcrenewal.blogspot.com/2014/02/cant-this-be-avoided-how-corporate.html">discussed</a> in more detail in February, 2014, <blockquote class="tr_bq">Documents made public as part of patients’ Pradaxa suits showed Boehringer officials didn’t disclose to U.S. regulators a data analysis that indicated the blood-thinning drug may have caused more fatal bleeding after it was cleared for sale than in a study used to win approval.  </blockquote> <a href="http://www.nytimes.com/2014/05/29/business/international/german-drug-company-to-pay-650-million-to-settle-blood-thinner-lawsuits.html">Per </a>the New York Times, Boehringer Ingelheim executives continued to maintain <blockquote class="tr_bq">that it stood behind the safety and efficacy of Pradaxa and continued to believe that the lawsuits lacked merit, but that settling the case allowed the company to move on. 'Time and again, the benefits and safety of Pradaxa have been confirmed,' said Desiree Ralls-Morrison, senior vice president and general counsel of Boehringer Ingelheim USA.</blockquote> This is typical of most legal settlements involving large health care organizations, whether they end lawsuits brought by private parties or by the US government.  The settlements often allow the parties to continue to disagree, do not establish guilt or innocence, but leave one to wonder why executives would pay so much of admittedly other peoples' money just to "move on" without upholding their or their companies' honor, especially when documents revealed and legal findings made in cases prior to settlement remain unchallenged. So this settlement also comes after December, 2013, as we discussed <a href="http://hcrenewal.blogspot.com/2013/12/a-second-order-cover-up-judge-finds.html">here</a>, December, when a judge <blockquote class="tr_bq">ordered Boehringer to pay a $931,000 fine in December for failing to preserve 'countless' files on Pradaxa’s development and marketing. Patients’ lawyers say Boehringer should have placed an effective 'litigation hold' on the documents, forcing employees to preserve them.</blockquote> (The above <a href="http://www.bloomberg.com/news/2014-05-28/boehringer-pays-650-million-to-end-blood-thinner-cases.html">per Bloomberg</a>.)  That finding, which the settlement does not dispute, does not fill one with confidence about the openness and transparency of Boehringer Ingelheim managers. Also the settlement does not refute documents released during this litigation which suggested that Boehringer Ingelheim personnel tried to influence, or manipulate a company sponsored research paper to prevent it from contradicting the company's official marketing message that Pradaxa administration does not require monitoring of patients with blood tests (as we discussed <a href="http://hcrenewal.blogspot.com/2014/02/cant-this-be-avoided-how-corporate.html">here</a>).     Note further that this case comes only a few years after a case in which Boehringer Ingelheim settled allegations of deceptive marketing of drugs other than Pradaxa, as we discussed <a href="http://hcrenewal.blogspot.com/2012/10/just-another-day-at-office-boehringer.html">here</a>. Medtronic Settles Suit Alleging Kickbacks to Physicians The most extensive and colorful <a href="http://www.startribune.com/business/260978651.html">report</a> was in the Minneapolis Star-Tribune, <blockquote class="tr_bq">Medtronic Inc. will pay the U.S. Justice Department $9.9 million to settle a whistleblower lawsuit that accused the company of paying kickbacks to doctors for using its defibrillators and pacemakers. The alleged kickbacks, according to the newly unsealed suit, included 'gifts of wine and alcohol' and 'trips to strip clubs' paid for by the Fridley-based company. The lawsuit also says Medtronic paid to fly doctors to events in San Francisco, Las Vegas, New Orleans, New York, Minneapolis and other cities that some physicians used as 'a free vacation.'</blockquote> More colorful details, <blockquote class="tr_bq">The lawsuit, whose details remained secret until Tuesday, describes Medtronic business plans with names such as 'Project Wildfire' that had sales representatives offer 'cash payments, expensive trips and meals, expensive gifts and entertainment to physicians as kickbacks in exchange for the physicians’ agreement to implant Medtronic devices.' The lawsuit alleged that Medtronic 'funneled millions of dollars in unrestricted grant money to physicians' to get them to encourage the use of Medtronic defibrillators and pacemakers in patients whose 'mild heart failure symptoms did not meet [Food and Drug Administration] criteria for an implantable device.' Those procedures were not only unnecessary, the suit alleged, but potentially dangerous. The suit describes payments of thousands of dollars in speaking fees to doctors for attending dinners at which they spoke for only a few minutes, if at all. In other cases, Medtronic allegedly prepared entire presentations that physicians offered almost verbatim. The suit talks of a plan that 'instructed sales representatives to personally review patient charts in friendly doctor’s offices' and to flag those patients the sales representative 'felt should receive an implant.'</blockquote> Note that commercially supplied "unrestricted grant money" is now the lifeblood of many ostensibly academic continuing medical education (CME) programs, but this case suggests that corporate executives may believe they are paying such money to get doctors to use their products.  Note further that many physicians defend their receipt of money in payment of talks they have given on behalf of commercial firms as fair payment for providing unbiased education, but this case suggests that corporate executives may believe they are paying such money for marketing, and/or to get the supposedly unbiased physician speakers to use their products.  Once again, the settlement did not resolve the allegations. <blockquote class="tr_bq"> Medtronic said it did not admit that any of its activities were improper or illegal and that the settlement would bring to a close a long-running review of events dating from 2001 to 2009.</blockquote> Also, <blockquote class="tr_bq"> Asked to comment specifically on the strip club allegations and the accusation that it financially facilitated unnecessary implantations, Medtronic reiterated that its $9.9 million payment was not an admission that it had done anything illegal or improper.</blockquote> See my comments above.  Why would executives with even the slightest ability to feel shame not contest such allegations if they were untrue?  But maybe many of today's corporate health care executives are not capable of feeling shame, and of course they get to pay off these lawsuits with other peoples' money. By the way, this is just one of many Medtronic settlements.  As Bloomberg <a href="http://www.bloomberg.com/news/2014-05-28/medtronic-settles-suit-over-heart-device-kickback-claims.html">summarized</a>, <blockquote class="tr_bq"> Medtronic agreed in 2007 to pay about $130 million to settle consumer suits accusing the device maker of hiding defects in its defibrillators. The company agreed to a $268 million settlement of suits in 2010 over allegations that fractured wires in another line of defibrillators caused at least 13 patient deaths.</blockquote> In fact, Medtronic has provided our blog with <a href="http://hcrenewal.blogspot.com/search/label/Medtronic">lots of material</a>.  We first <a href="http://hcrenewal.blogspot.com/2006/01/medtronics-payments-to-doctors-too.html">discussed</a> detailed and vivid allegations that Medtronic had been paying off doctors starting in 2003 here in 2006.  Medtronic has been involved in other lawsuits alleging various kinds of deception. -  In 2011, it settled for $23.5 million two other federal lawsuits alleging it paid kickbacks to encourage physicians to implant its devices (look <a href="http://hcrenewal.blogspot.com/2011/12/medtronic-settles-yet-again.html">here</a>).   - In 2008, Medtronic subsidiary Kyphon settled a suit for $75 million and signed a corporate integrity agreement for allegations that it defrauded Medicare through a scheme that lead to excessive hospitalization for patients who received the company's spine surgery device (link <a href="http://hcrenewal.blogspot.com/2008/05/corporate-integrity-agreement-for.html">here</a>) - In 2006, Medtronic subsidiary Sofamor Danek settled for $40 million allegations that it gave kickbacks to doctors in the form of sham consulting fees and lavish trips (look <a href="http://hcrenewal.blogspot.com/2011/12/medtronic-settles-yet-again.html">here</a>). Yet we are now writing at the end of May, 2014, and Medtronic is still settling lawsuits involving vivid allegations of payoffs to physicians, and its executives are still saying nothing to see here, move on. Summary These sorts of cases provide evidence that large health care corporations, including not just pharmaceutical companies, but biotechnology and medical device companies, commonly use deceptive and unethical practices to market their products.  Such marketing lets them charge high, even outrageous prices and sometimes results in patients getting expensive treatments that do them no good, or worse, that do more harm than good.  Some of the executives of these companies doubtless got large bonuses, and may have gotten millions in compensation partially because of the sales generated by these practices.  However, they get to walk away from such lawsuits without any personal accountability, just by paying out a few millions, or billions, of the company's, that is, other peoples' money.  They get do pay that money without any other explanation that it eliminates distractions and allows them to move on (with whatever they have already made). The more this goes on, the more health care dysfunction continues, and the more the health care oligarchy prospers.  As we have written many times, <blockquote class="tr_bq">penalties that only appear to be (relatively small) costs of doing business are unlikely to deter future bad behavior. Until the people who actually authorized, directed and implemented the bad behavior have to suffer some negative consequences, expect the bad behavior to continue.  Note that each of the companies discussed above have had their previous ethical lapses discussed in previous Health Care Renewal posts. The continuing march of <a href="http://hcrenewal.blogspot.com/search/label/legal%20settlements">settlements</a>, and sometimes <a href="http://hcrenewal.blogspot.com/search/label/crime">criminal</a> convictions involving major health care organizations should be regarded merely as providing a floor to estimates of the extent of bad behavior by large health care organizations. Bad behavior may not be reported, or lead to legal action, and legal action may not lead to settlements or convictions. However, it is amazing how many organizations that were once regarded as exemplary have had to settle, or plead guilty, or been convicted. When it comes to health care's leadership, society seems to have acceded to defining deviancy down. Until we start holding health care leaders to high standards, expect their organizations not to uphold high standards.</blockquote> (That version was from 2010, posted <a href="http://hcrenewal.blogspot.com/2010/10/last-weeks-scandals.html">here</a> re Medtronic's 2010 settlement. You heard it here first.  Medtronic is still settling, and according to its <a href="http://phx.corporate-ir.net/phoenix.zhtml?c=76126&p=IROL-secToc&TOC=aHR0cDovL2FwaS50ZW5rd2l6YXJkLmNvbS9vdXRsaW5lLnhtbD9yZXBvPXRlbmsmaXBhZ2U9OTAwMDI5NiZzdWJzaWQ9NTc%3d&ListAll=1">most recent proxy</a>, from 2013, the annual total compensation of its CEO was last reported to be $8,975,886.)

Fool Me Twice? - Boehringer Ingelheim, Medtronic Settle Lawsuits Alleging Deceptive Marketing

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03 Jun 2014

Sovaldi - a "Revolution" in Clinical Care, or in Marketing and Public Relations?

The continuing public discussion of the sky high price Gilead has set for Sovaldi (sofosbuvir,) its new antiviral drug for hepatitis C, continues to avoid considering the lack of good evidence that the drug is as safe and effective as its proponents claim. We first <a href="http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html">posted</a> about the Sovaldi debate on March 27, 2014, and its focus on price rather than the quality of the evidence underlying loud claims about the miraculous qualities of the drug.  We suggested that there is no good evidence supporting claims that most hepatitis C patients have very bad outcomes if untreated, treatment prevents most bad outcomes, Sovaldi cures nearly all patients, and Sovaldi has very few side effects. In a subsequent post we wrote that initially, "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." On May 7, we <a href="http://hcrenewal.blogspot.com/2014/05/some-authoritative-skepticism-about.html">noted</a> an assessment by the German Institute for Quality and Efficiency in Health Care (IQWiG) of information submitted by "industry" (presumably Gilead) to the German government.  This assessment found multiple problems with the evidence, including limited generalizability, problems with randomization, lack of information about important outcomes, and lack of ability to quantify benefit.   Also  the US based Institute for Clinical and Economic Review noted that there was little evidence that compared to previous treatments, Sovaldi is better, and no evidence that Sovaldi produces cures in the long term. Nonetheless, the notions that the evidence supporting Sovaldi (and perhaps other similar drugs) is weak, and that the drugs therefore should not yet be considered miracle cures have not seemingly affected the public discussion.  Examples of the Latest Discussion Washington Post/ Kaiser Health News On May 12, 2014, in an <a href="http://www.kaiserhealthnews.org/stories/2014/may/12/medicare-struggling-with-hepatitis-c-cure-costs.aspx">article</a> on the dilemma the drug's US price of $1000/ pill presents to Medicare, Richard Knox wrote this about a patient with the infection: <blockquote class="tr_bq">Previous drug treatments didn't clear the virus from Bianco's system. But it's almost certain that potent new drugs for hep-C could cure him. </blockquote> In other words, the article asserted that Sovaldi and similar drugs cure nearly everyone with hepatitis C, even those not cured by previous treatment.  Reuters On May 20, 2014, in an <a href="http://www.reuters.com/article/2014/05/20/us-insurance-gilead-sciences-drugcosts-idUSKBN0E029U20140520">article</a> about how US health insurers are balking at the price of Sovaldi, was this statement by the main trade organization for US for-profit health care insurers, America's Health Insurance Plans (AHIP), <blockquote class="tr_bq">Sovaldi has shown tremendous results, and it's the kind of medical innovation we need to sustain. </blockquote> In the article's text was the assertion, <blockquote class="tr_bq">The new drug has demonstrated an ability to cure well over 90 percent of patients in just 12 weeks or less with few side effects. Prior to the Sovaldi approval, hepatitis C treatments took 24 or 48 weeks, cured about 75 percent of patients and involved many more pills as well as injectable interferon that causes flu-like symptoms and other side effects that led many people to avoid or discontinue treatment.</blockquote> In other words, the article asserted that Sovaldi can cure over 90% of patients compared to the cure rate of 75% provided by previously available treatments, and implied Sovaldi has fewer side effects. CNBC On May 22, 2014, in an <a href="http://nbr.com/2014/05/22/the-84000-question-will-focusing-on-drug-prices-rein-in-costs/">article</a> on the high costs of new drugs, a quote from Dr Douglas Dieterich, "a liver disease specialist at Mount Sinai Hospital," who "has consulted for pharmaceutical companies, including Gilead," appeared, <blockquote class="tr_bq">I don’t think there’s any question that treating patients with hepatitis C will lower overall health-care costs in the coming 20 years,... If we could get rid of the liver disease in these patients with hepatitis C, prevent them from dying of liver cancer, cirrhosis and liver failure, then there’s no question the cost will be less.</blockquote> The implication was that the new drugs can get rid of the disease, that is, cure it, and in doing so prevent early mortality, cirrhosis, and liver failure. CTV The discussion of Sovaldi in Canada seems similar. On May 25, 2014, an <a href="http://www.ctvnews.ca/health/hepatitis-c-drugs-show-promise-but-price-is-too-high-for-most-patients-1.1837917">article</a> on the high cost of hepatitis C drugs in Canada from CTV, "Canada's largest private broadcaster," (look<a href="http://www.ctv.ca/About/Corporate-Info/About.aspx"> here</a>) quoted a Canadian physician, <blockquote class="tr_bq"> Dr. Curtis Cooper, director of the viral hepatitis program at the Ottawa Hospital, said the drugs Sovaldi and Galexos offer a revolution for patients with the hepatitis C virus (HCV). 'It only requires 12 weeks of treatment and (they) are producing cure rates of 90 to even 100 per cent,' he told CTV News.</blockquote><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"></div> And later, addressing the treatment of a particular patient, <blockquote class="tr_bq">We're talking about curative therapies, which could potentially save her from liver failure, save her from liver cancer</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;">Again, the assertions were that the drug cures 90%, maybe 100% if patients, and that cure will prevent liver failure and cancer.</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;">Is There Any Good Evidence?</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;">Again, while there is much discussion, and some outrage over the $1000 per pill price of Sovaldi in the US (in Canada, a bargain at Canadian $650 per pill), all the discussion seems to assume that the pill is really a "revolution" (as per CTV), that provides</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">- cure rates of 90 - 100%, much better than previously available treatments</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">- lower adverse effect rates than than those caused by previously available treatments</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">-  prevention of complications of hepatitis C, including cirrhosis, liver failure, liver cancer, and early death.</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;">I have found just one recent media article that throws a bit of evidence-based cold water on these claims, and refers to a new systematic review that should be generating a lot of interest, and provoking much more skepticism about the drug, but so far is not. </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 Single Skeptical Article </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;">On May 22, 2014, a MedPage Today article noted a new systematic review of sofosbuvir (Sovaldi) that had a very different message from the articles above.  In 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;"><blockquote class="tr_bq">The evidence base for one of the star hepatitis C drugs is poor and the guidelines for its use are flawed, according to a report obtained by the <a href="http://medicaiddirectors.org/about" target="_blank">National Association of Medicaid Directors</a>. According to the report, studies of sofosbuvir (Sovaldi) are generally of poor quality, mostly directed by the drug's maker, and don't answer key questions, including whether the drug is better and safer than the current standard of care. The only available guidelines for its use -- guidelines created by the <a href="http://www.aasld.org/" target="_blank">American Association for the Study of Liver Diseases</a> and the <a href="http://www.idsociety.org/" target="_blank">Infectious Diseases Society of America</a> -- are 'methodologically flawed,' according to the report, which was prepared by the<a href="http://www.ohsu.edu/xd/research/centers-institutes/evidence-based-policy-center/" target="_blank"> Center for Evidence-Based Policy</a> at Oregon Health and Science University in Portland (OHSU). In addition, their authors and sponsors had 'multiple and significant conflicts of interest,' the report argued.</blockquote> The Report from the Center for Evidence-Based Policy The report is public, available without cost direct form the Center (email < centerebp@ohsu.edu> ), although not yet directly available on the web.  It directly addresses all four of the major claims made about Sovaldi that we discussed in our <a href="http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html">first post</a> n the topic. </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;">- Most hepatitis C patients have very bad outcomes if untreated The report cited the best data about outcome prevalence, <blockquote class="tr_bq">approximately 15% to 25% of people infected with HCV will clear the virus during the acute stage without treatment.  Seventy-five to 85% of infected individuals will develop a chronic HCV infection, and 60% to 70% of patients with chronic infection will develop chronic liver disease.  Over 20 to 30 years, 5% to 20% of infected patients will develop cirrhosis and 1% to 5% will die of cirrhosis or liver cancer.</blockquote> Although a majority of chronically infected patients will develop some liver disease, only a minority will develop cirrhosis or liver cancer. </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;">- Treatment prevents most bad outcomes The report stated, <blockquote class="tr_bq">Because of the slow progression of the disease, clinical trials have not evaluated these patient-important conditions [cirrhosis, hepatocellular carcinoma, decompensated liver disease, liver transplant, or death] as trial outcomes.  Instead a surrogate endpoint of sustained virologic response (SVR) has been used to measure success of treatment.  The SVR is defined as undetectable HCV-ribonucleic acid (RNA) levels.  The standard measure of treatment success has been SVR at 24 weeks post treatment (SVR24). Several long-term studies of patients with chronic HCV infection have shown an association between achieving SVR24 and patient-important clinical outcomes.</blockquote> So there is no direct evidence that treatment prevents any of the bad outcomes.  There is only indirect evidence that treatment may reduce the rate of some bad outcomes.  For example, <blockquote class="tr_bq">A 2014 observational study of a VA population found that ... the 5180 (4%) of patients who were able to achieve an undetectable viral load with interferon-based treatment had a 45% reduction in the risk of death ... and 27% reduction in the composite clinical endpoint ... of newly diagnosed cirrhosis, HCC [hepatocellular carcinoma], or liver related hospitalization.</blockquote> However, at best, based on an observational analysis that could have been biased, treatment only may have prevented a minority of bad outcomes. </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;">- Sovaldi cures nearly all patients</div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"> As we noted earlier, there have been only two randomized controlled trials published that compared sofosbuvir with anything else.  One compared it to placebo, and one was the trial we discussed earlier that compared it sofosbuvir with ribavirin to pegylated interferon with ribavirin.  (Look <a href="http://hcrenewal.blogspot.com/2014/03/too-good-to-be-true-sovaldi-kerfuffle.html">here</a>.)   <blockquote class="tr_bq">All other studies were designed to refine drug dose, drug combination or duration of treatment.</blockquote> Also, <blockquote class="tr_bq">All studies were rated as having a high risk of bias.  No study was judged to have good applicability....  The overall summary judgement for each of the published studies yielded a rating of poor.</blockquote> Furthermore, the review found even more problems with the only study that compared sofosbuvir to active treatment (peg-interferon) than we did.  In particular, that study did not compare sofosbuvir with ribavirin to the current standard regimen of PEG plus weight-based ribavirin.  Instead, it compared it to a regimen that included low dose ribavirin.  By comparing sofosbuvir plus a higher dose or ribavirin, an active drug, to a peg-interferon plus a lower dose of ribavirin, the study design seemed designed to artificially enhance the efficacy of the sofosbuvir containing regimen.   Furthermore, the study did not assess the measure of sustained viral response at 24 weeks currently accepted as the best surrogate variable.  Instead it used SVR at 12 weeks, which may be correlated with SVR24 but is often higher. Thus this choice of endpoint seemed designed to increase the apparent efficacy of the regimens it evaluated.  So sofosbuvir has so far been compared to another active anti-viral regimen against hepatitis C in only one study.  That study was poorly designed and implemented, and its problems seemed likely to enhance the apparent efficacy of sofosbuvir.  Nonetheless, that one study did not show that sofosbuvir was more efficiacious, or safer than peg-interferon. </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;">- Sovaldi has very few side effects. </div><div style="background-color: white; border: medium none; color: black; overflow: hidden; text-align: left; text-decoration: none;"></div>The review had this summary, <blockquote class="tr_bq">The FDA compiled reports of adverse events from four trials....  There were no treatment-related deaths reported [note that we found there were deaths in the one trial that compared sofosbuvir to PEG, look <a href="http://hcrenewal.blogspot.com/2014/04/knee-deep-in-hoopla-triumph-of-medical.html">here</a>]. Approximately 78% of patients receiving placebo, 88% of patients on SOF + RBV treatment and 95% of patients receiving PEG + SOF +RBV reported a side effect from treatment.  The most common side effects were fatigue, anemia, nausea, rash, headache, insomnia and pain....</blockquote> Thus it seems likely that Sovaldi has a lot of side effects, and whether it has fewer than standard treatment is unclear.  Furthermore, <blockquote class="tr_bq">studies on sofosbuvir were small, included populations that were healthier than the general hepatitis C population, were of short duration and had limited follow-up.  In many of the studies, the manufacturer was responsible for recording and reporting adverse events.  In general, reporting of adverse events is often incomplete and discrepancies between clinical trial reports and publications are common....  All of these factors would lead to a bias in under-reporting the true nature of adverse events.</blockquote> Thus there is no good evidence that sofosbuvir has few side effects, or is dramatically safer than older treatments. Summary While there continues to be concern, if not outrage, that the latest treatment for hepatitis C is priced at $1000 per pill, most of those expressing concern seem to assume that the pill is a wonder drug, promising nearly everyone a cure without major side effects.  However, as we first noted in March, 2014, there is no strong evidence to that effect.  In fact, now three skeptical looks at the evidence by people with more resources and perhaps more expertise than we possess have shown similar conclusions. It is a tribute to the power of the <a href="http://hcrenewal.blogspot.com/search/label/anechoic%20effect">anechoic effect</a> that there has been almost no recognition by physicians and other health professionals, journalists, and most amazingly, insurance companies who stand to lose billions paying for Sovaldi, that there is little good evidence that Sovaldi works, much less is superior to previous treatments.  Instead, even America's Health Insurance Plans thought the drug had "tremendous results," not very different from the assertion by the drug's manufacturer that the drug provides "a finite cure," (as reported by Reuters).  One might think that the insurance companies have enough money to invest in some real evidence-based medicine experts who could provide a skeptical assessment of the pricy new drugs and devices for which these companies may pay.  Is it that the commercial insurers are so now so dominated by generic managers who know nothing about health care, medicine, or biomedical science, much less evidence-based medicine that they are unable to resist the marketing and public relations hype? 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. As we have said until blue in the face, true health care reform would bring some skeptical thinking and regard for evidence and logic into the health policy discussion.

Sovaldi - a "Revolution" in Clinical Care, or in Marketing and Public Relations?

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28 May 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

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