Pfizer's Latest International Pfiascos - Charges of Anti-Competitive Practices, Inflated Prices, Deception and Secrecy

Many big health care organizations seem to just be unable to keep out of trouble, and the bigger they are, the more kinds of trouble.  Pfizer Inc, considered to be one of the world's largest pharmaceutical companies, has supplied us with plenty of stories.  Enough new stories about Pfizer have accumulated since last year to do a roundup.   

Presented in chronological order....

Italy Demands Damages from Pfizer for Anti-Trust Violations

This story came out in May, 2014, via Reuters,

Italy said on Wednesday it was seeking more than a billion euros in damages from multinational drug companies following a ruling by the country's antitrust authority that their policies had been detrimental to Italy's national health service.

The health ministry said in a statement it was requesting a total 1.2 billion euros ($1.6 billion) from Novartis and Roche for the damages incurred in 2012-2014, and was requesting 14 million euros from Pfizer.

It cited several recent antitrust rulings that the companies' repeated anti-competitive actions had caused the national health service 'considerable damage'.

The specific charges against Pfizer were:

Italy's state council, the highest administrative court, in February ruled that Pfizer had abused its dominant position relating to the glaucoma drug Xalatan 'with a clear and persistent intention to suppress competition'.

At least in English language news sources, I have not seen how this turned out, but note that this was apparently an administrative court finding, not just a prosecutor's allegation.

Pfizer Accused of Overcharging for Pediatric Vaccines

This appeared in January, 2015, here via Ed Silverman's PharmaLot blog (when it was affiliated with the Wall Street Journal),

In a bid to widen access to vaccines, Doctors Without Borders is calling on Pfizer and GlaxoSmithKline to lower the prices for their pneumococcal vaccines to $5 per child in developing countries. The non-profit claims the drug makers are 'overcharging' donors and developing countries for vaccines that 'already earn them billions of dollars in wealthy countries.'

The non-profit, which regularly advocates for lower prices for medicines, maintains that, in general, the price to vaccinate a child against several diseases is now a 'colossal' 68 times more expensive than in 2001. In a new report, Doctors Without Borders attributes 45% of that increased cost to the price tags for pneumococcal vaccines sold by the drug makers. Pneumococcal disease, by the way, kills about 1 million children per year, mostly in poor and developing nations.

Think about the children.

The non-profit maintains that the current price tag makes it difficult to supply the vaccine to large numbers of children, and the drug makers have already received $1 billion in incentives to manufacturer the vaccine for developing countries. 'We think it’s time for Glaxo and Pfizer to do their part to make vaccines more affordable for countries in the long term, because the discounts the companies are offering today are just not good enough,' says Malpani in a statement.

Moreover, Doctors Without Borders warns that pricing may eventually make it harder for a growing number of middle-income countries to afford vaccines. Over time, some of these countries will eventually ‘graduate’ from the subsidized vaccine pricing established by Gavi and, when that happens, Doctors Without Borders estimates costs may rise up to six times what is the countries pay today.

The post included a statement from Pfizer about how hard it is to manufacture the vaccine, and an update to the post included a statement from Pfizer that it was already selling its pneumococcal vaccine, Prevenar 13, below cost to GAVI, which buys up vaccines and provides them to poor countries. A week later, again via (the old version of) PharmaLot, Pfizer announced an additional 6% price cut. Furthermore, Bill Gates, whose foundation supports GAVI, insisted that cutting vaccine prices would discourage pharmaceutical companies from investing in vaccine research and supplying products to poor countries, according to the Guardian.

However, neither Pfizer nor Mr Gates acknowledged how much money Pfizer already is making from Prevenar in developed countries, amounts which likely do far more than offset any losses in poorer countries. Specifically, in July, 2015 FierceVaccines reported that

The world's biggest vaccine by sales--Prevnar 13--just keeps getting bigger. And in doing so, the shot helped Pfizer notch 44% vaccines growth for the second quarter as the unit saw sales grow from $1.09 billion in last year's Q2 to $1.58 billion during the period this year.

For the quarter, the superstar pneumococcal disease-blocker notched a U.S. sales increase of 87% versus the same period last year, a jump Pfizer CEO Ian Read attributed to 'continued strong uptake' in U.S. adults.

Also,

Prevnar 13, which reeled in $4.29 billion in sales last year, is expected to grow to $5.83 billion in 2020 and remain atop the vaccines sales charts.

And,

The company is also working 'country by country' to broaden the vaccine's reach in G7 countries....

So there seems to be some evidence in support of the Doctors Without Borders claim that Pfizer could easily afford some small losses selling vaccines for use by poor children in less developed countries while it makes billions of dollars from vaccine sales in developed countries.  


Pfizer Settles Shareholder Suit for $400M

This settlement was just the latest that has resulted from allegations of illegal drug marketing by Pfizer.  As reported again by the redoubtable Ed Silverman in the old version of PharmaLot,

Pfizer has reached an agreement in principle to pay $400 million to settle a class-action securities lawsuit that alleged the drug maker illegally marketed several medicines and, subsequently, caused investors to lose money, according to a filing with the U.S. Securities and Exchange Commission.

The lawsuit alleged that, between January 2006 and January 2009, Pfizer marketed several drugs on an off-label basis. The medicines included the Bextra painkiller that was withdrawn from the market in 2005; the Geodon antipsychotic; the Zyvox antibiotic and the Lyrica epilepsy treatment.

The lawsuit, which was filed in federal court in 2010, alleged that the sales boost the drug maker received from the marketing prompted Pfizer executives to make 'false and misleading statements about Pfizer’s financial performance and sales practices [that] caused Pfizer stock to trade at artificially inflated prices.'

This settlement followed an even larger one back in 2009 when,

the drug maker revealed plans to pay $2.3 billion to resolve criminal and civil allegations that these drugs were marketed illegally.

We discussed that settlement in 2009 here, here, and here.  Note that the 2009 settlement included a guilty plea to a criminal charge (albeit to a misdemeanor), and was of allegations including paying kickbacks to doctors for use of Pfizer drugs.  So this additional settlement of deceiving investors just ices that cake. 

UK Competition and Markets Authority Stated Pfizer Abused Market Dominance

This story appeared in August, 2015, via the Telegraph,

The Competition and Markets Authority (CMA) has issued a statement of objections alleging the companies breached UK and EU law by raising the prices they charged for phenytoin sodium sold to the NHS.

In particular,

The CMA says that for years industry giant Pfizer, which is listed in the US, and Flynn, a Stevenage-based company, between them sold the drug at a price up to 27 times higher than it had been previously priced.

Before September 2012, Pfizer manufactured and sold phenytoin sodium capsules to UK wholesalers and pharmacies under the brand name Epanutin.

Pfizer then sold the UK distribution rights for Epanutin to Flynn, which 'de-branded' the drug and started selling its version in September 2012. Pfizer continued to manufacture the drug, which it sold to Flynn at prices the CMA says were 'significantly higher' than those at which it had previously sold Epanutin.

The CMA claims Pfizer sold the drug at between 8 and 17 times its historic prices to Flynn, which then sold on phenytoin sodium at between 25 to 27 times more than the prices previously charged by Pfizer.

Before Flynn bought the rights for Epanutin, the NHS spent about £2.3m on phenytoin sodium capsules a year, according to the CMA. After the deal this spend rose to just over £50m in 2013 and more than £40m in 2014.

While the CMA findings were apparently "provisional," but the agency has the power to find that the law has been breached and "has the power to fine then up to 10pc of their global annual turnover - last year Pfizer had revenue of almost $50bn."  So this is the second government finding of anti-competitive behavior by Pfizer in a little over one year.

Pfizer Resists AllTrials Calls for Transparency

Late in August, 2014, per the Guardian,

Pfizer, one of the world’s largest pharmaceutical groups, has said it will resist demands from investors and transparency campaigners that it disclose results from all historical drug trials.

We have been discussing how pharmaceutical, biotechnology, and device companies have manipulated the clinical trials they sponsor to increase the likelihood that the results make their products look good, and may suppress trials whose results cannot be made to look good enough. This clinical research suppression and manipulation can lead to poor clinical decisions, may harm patients, and abuses the trust of patients who volunteer to participate in clinical research. This situation has led to the AllTrials campaign to make clinical research transparent (look here). However,

Pfizer said it had a 'longstanding commitment to clinical trial transparency' and it already published data for trials from 2007. Requests for earlier data are considered on an individual basis. But it added: 'We don’t believe that further investment beyond this would offer value to patients, health services or to our shareholders.'

This despite arguments above about the harms of research suppression.  Given how much money Pfizer has spent on lawsuits, including one above about allegations of its management's deception of shareholders, one might think it would be worth it for management to make a little investment in transparency.

Pfizer Found to Have Withheld Reports of Adverse Drug Events in Japan

Finally, reported in September, 2015 by in-PharmaTechnologist.com,

Pfizer failed to report hundreds of serious adverse drug reactions (ADRs) in the required timeframes according to Japan’s Ministry of Health, Labor and Welfare (MHLW) which has issued the US firm with a business improvement order. 

That website has copy protection so I cannot quote further, but the order involved 11 drugs, including Enbrel and Lyrica.  So here is yet another example of a government agency finding that Pfizer was less than transparent, if not overtly deceptive.

Summary

So in a little more than a year, Pfizer has been accused of anti-competitive practices raising drug costs in Italy, excess pricing of vaccines for use by poor children in undeveloped countries, deceiving its own investors about illegal marketing activities in the US, abuse of market dominance leading to excessive drug costs in the UK, stonewalling clinical trial transparency measures globally, and failing to disclose adverse drug effects in a timely manner in Japan.  This is on top of an already impressive record of misbehavior (See our summary of Pfizer mischief at the end of the post.)

However, as seems usual these days, no one at Pfizer who might have authorized, directed or implemented any of this bad behavior has ever seemingly paid any sort of penalty for it.  Instead, while this was going on, the top leadership of Pfizer just gets richer faster and faster.  In fact, in March, 2015, the Wall Street Journal reported the current Pfizer CEO's total compensation in 2014,

Pfizer Inc. said Thursday that Chief Executive Ian Read’s total compensation rose 23% last year, lifted by an increase in pension value that offset a reduced annual bonus and equity award.

Furthermore,

Mr. Read’s 2014 pay package totaled $23.3 million. The board raised the CEO’s salary to $1.83 million from $1.79 million but decreased his annual bonus by $400,000 and his equity award by nearly $1 million despite concluding that Mr. Read’s leadership during the year was 'outstanding.'

[Even though] Over the course of 2014, shares in the New York-based pharmaceutical company gained about 2% amid a 4% decrease in revenue.

It is not obvious that the rise in CEO pay is even remotely correlated to any rise in share-holder value.  Moreover, there seems to be a total disconnect between the rewards given the CEO and the ethical record of the company he leads, especially since Pfizer, which calls itself "one of the world's premier pharmaceutical" corporations, announces its aspirations thus,

we at Pfizer are committed to applying science and our global resources to improve health and well-being at every stage of life. We strive to provide access to safe, effective and affordable medicines and related health care services to the people who need them.

Never mind all those pesky allegations of overpricing, anti-competitive practices, deception and opaqueness, and never mind that current executives are becoming exceedingly risk in part from the continuation of such practices.  So it seems the board of Pfizer will just continue handing its executives piles of money, despite, or for all I know, because of the company's continuing bad behavior.  Given these incentives, is it any wonder that the bad behavior continues?  Pfizer seems to be just another example - albeit a big one - of how health care is dominated by an oligarchy of unaccountable leaders who continue to demonstrate their impunity hidden by aspirational but hollow public relations and marketing.

Of course, it is doubtful such bad behavior would continue if there risks of external penalties, e.g., from law enforcement.  But there never seem to be any.

In the past, US law enforcement authorities have announced they would use the responsible corporate officer doctrine, a legally tested rationale for prosecuting corporate managers for bad behavior by those who report to them (e.g., in 2010, look here),  But it seems they have never done so, at least in cases involving large health care organizations.  Last week, the US Department of Justice announced it would start going after executives of companies that misbehave, and would press the companies to give up the name of responsible executives in exchange for more lenient treatment of the companies themselves (e.g., see this report in the NY Times).  Meanwhile, however, the march of legal settlements for bad behavior in health care continues, absent any penalties for organizational leaders who might have authorized or directed it, much less for those who simply put incentives in place to foster bad behavior while looking away from what those incentives inspired.    

I hope these current promises by law enforcement officials are not as hollow as earlier ones, because continuing our society's continuing failure to rein in corrupt business practices via law enforcement and regulation may lead a desperate populace to more radical approaches. The UK Labor Party just elected a Marxist leader (see this Reuters report.)  One wonders how long it will be before anger at the larger oligarchy, of which health care leadership is merely a part, boils over in other countries, and in more radical ways.

Instead, we continue to advocate for true health care reform with the immediate priority of changing how health care organizations are led, and ensuring leadership that upholds health care values, is willing to be accountable, and is open, honest, transparent and ethical.  We still may have time to reform.  But the reform will have to be big and true.  If not, moderate voices may be drowned out, and the results may be worse than anyone could imagine.

Appendix - Pfizer's Previous Settlements


For all our posts on Pfizer, look here.

In the beginning of the 21st century, according to the Philadelphia Inquirer, Pfizer made three major settlements,
- In 2002, Pfizer and subsidiaries Warner-Lambert and Parke-Davis agreed to pay $49 million to settle allegations that the company fraudulently avoided paying fully rebates owed to the state and federal governments under the national Medicaid Rebate program for the cholesterol-lowering drug Lipitor.
- In 2004, Pfizer agreed to pay $430 million to settle DOJ claims involving the off-label promotion of the epilepsy drug Neurontin by subsidiary Warner-Lambert. The promotions included flying doctors to lavish resorts and paying them hefty speakers' fees to tout the drug. The company said the activity took place years before it bought Warner-Lambert in 2000.
- In 2007, Pfizer agreed to pay $34.7 million in fines to settle Department of Justice allegations that it improperly promoted the human growth hormone product Genotropin. The drugmaker's Pharmacia & Upjohn Co. subsidiary pleaded guilty to offering a kickback to a pharmacy-benefits manager to sell more of the drug.

Thereafter,
- Pfizer paid a $2.3 billion settlement in 2009 of civil and criminal allegations and a Pfizer subsidiary entered a guilty plea to charges it violated federal law regarding its marketing of Bextra (see post here).
- Pfizer was involved in two other major cases from then to early 2010, including one in which a jury found the company guilty of violating the RICO (racketeer-influenced corrupt organization) statute (see post here).
- The company was listed as one of the pharmaceutical "big four" companies in terms of defrauding the government (see post here).
- Pfizer's Pharmacia subsidiary settled allegations that it inflated drugs costs paid by New York in early 2011 (see post here). 
- In March, 2011, a settlement was announced in a long-running class action case which involved allegations that another Pfizer subsidiary had exposed many people to asbestos (see this story in Bloomberg).
- In October, 2011, Pfizer settled allegations that it illegally marketed bladder control drug Detrol (see this post).
- In August, 2012, Pfizer settled allegations that its subsidiaries bribed foreign (that is, with respect to the US) government officials, including government-employed doctors (see this post).
- In December, 2012, Pfizer settled federal charges that its Wyeth subsidiary deceptively marketed the proton pump inhibitor drug Protonix, using systematic efforts to deceive approved by top management, and settled charges by multiple states' Attorneys' General that it deceptively marketed Zyvox and Lyrica (see this post).
- In January, 2013, Pfizer settled Texas charges that it had misreported information to and over-billed Medicaid (see this post).
- In July, 2013, Pfizer settled charges of illegal marketing of Rapamune (see this post.)
- In April, 2014, Pfizer settled allegations of anti-trust law violations for delaying generic versions of Neurontin( see this post).
- In June, 2014, Pfizer settled another lawsuit alleging illegal marketing of Neurontin (see this post).

1:43 PM

Once More with Feeling - Amgen Again Settles Allegations of Misbranding, But Why Bother?

The Latest Settlement

Biotechnology giant Amgen has just reached another settlement of allegations that it unfairly, deceptively or misleadingly marketed its drug. Per the Los Angeles Times,

Amgen Inc. has agreed to pay $71 million to settle allegations by 48 state attorneys general that it improperly marketed two of its blockbuster drugs.

That is,

The states, including California, alleged that Amgen violated consumer protection laws by promoting the use of its anemia drug Aranesp for longer periods than the Food and Drug Administration had approved and by encouraging its use to treat anemia caused by cancer without FDA approval.

In addition, Amgen was accused of promoting its drug Enbrel as a treatment for mild plaque psoriasis even though it was approved only for severe plaque psoriasis, and for overstating the length of time that Enbrel effectively treats the disease.

This is the second settlement Amgen has made for improper marketing of Aranesp.

Three years ago, Amgen pleaded guilty to a single misdemeanor in federal court in New York for improperly marketing Aranesp. The drugmaker agreed to pay $150 million in criminal penalties and $612 million to resolve broader civil lawsuits, including allegations that Medicare, Medicaid and other government insurance programs were improperly billed.

At the time, federal prosecutors called the settlement 'the single largest criminal and civil False Claims Act settlement involving a biotechnology company in U.S. history.'

Although doctors can prescribe medications for off-label uses, drug companies are banned from promoting uses that aren't approved by the FDA, which has been at odds with some drugmakers over the issue.

This settlement seems to be just the latest in a very long procession of legal settlements  of allegations of apparent misbehavior by large health care organizations.  We have previously discussed many such settlements, how they serve as markers of ethical lapses by leaders of large organizations, and also how the failure of most of these settlements to provide meaningful penalties to those who presided over, directed, or implemented the bad behavior allows continuing impunity and fails to deter future bad behavior.  Many large organizations have made multiple such settlements in recent years, but have these settlements seem to have not promoted honest, transparent, accountable health care.   

Yet continuing government efforts to provide even these weak challenges to continuing bad behavior now appear under threat.

Is Misbranding a Crime?

The fundamental allegations in the original large Aranesp settlement were of misbranding (although the settlements with state government just announced were of violations of state laws prohibiting, as in the case of Connecticut, "unfair, deceptive or misleading" marketing practices.)  Marketing a drug or device for uses other than those approved by the US Food and Drug Administration (FDA) may be called "misbranding."

Whether misbranding should be considered a crime has lately become controversial.   Recently, an appeals court agreed with the notion that such marketing is constitutionally protected speech, as long as it is "truthful." (See discussion by Shannon Brownlee on the Lown Institute blog, and the NY Times news article.)  I am not a lawyer, so I will try not to deal with this constitutional argument at this time.  But most of the public discussion has focused on the narrow issue of whether misbranding is in fact protected free speech.

However, the case of the 'misbranding allegations agains Amgen suggest other issues worthy of consideration.

Promoting a Not Merely Ineffective, but Dangerous Drug

As we discussed here in 2012, Amgen pleaded guilty to one count of illegally marketing Aranesp, and agreed to pay a penalty of $762 million.  As we noted, the misbranding in this case was promotion of Aranesp for patients with cancer who were not receiving chemotherapy.  However, a growing collection of evidence suggested that epoetin drugs, a class in which Aranesp resides, increase the death rate in patients with various kinds of cancer.  On the other hand, Aranesp was never meant as a possible cure for cancer.  At best, its benefit is improvement of anemia, which might, just might improve how some patients feel in the short-term.  So it appears Amgen was promoting a dangerous drug without any evidence that the drug provided benefits that balanced the danger.  This appears very bad for patients.  The misbranding here was not some technical violation, but likely a deceptive effort that could have hurt patients, while profiting Amgen and its top executives.  The ethics here look much worse than the single guilty plea suggested.

Misbranding just refers to promoting a drug or device for uses that the FDA did not approve.  Some cases of misbranding could cause little more than inconvenience and added expense, but others could result in serious harm to patients.  Treating them all as misbranding removes important distinctions.

Allegations of Kickbacks

Furthermore, as discussed here in 2013, the 2012 settlement was not just about misbranding.  It was about kickbacks, that is bribes given to doctors by Amgen to induce them to prescribe a dangerous medication.  The settlement was arranged that Amgen did not admit to the alleged kicbkbacks.  But neither did it deny them, and the company apparently thought it was worth $762 million to avoid further dealing with these accusations, which nonetheless hang in the air.  So the ethics here now look even worse, invovling promoting a dangerous drug allegedly with bribery.


Furthermore, after news of the original Aranesp settlement came out, other stories of other settlements by Amgen appeared.  As we noted here,  in 2013, Amgen settled allegations that it also paid kickbacks to Omnicare and PharMerica to promote Amgen use in nursing homes and hospital.  It also settled charges that it inflated pricing data to obtain larger payments from Medicaid in multiple states for a variety of its drugs, including Aranesp.   Later in 2013, as we noted here, Amgen settled yet more charges that it gave kickbacks to doctors to promote one of its products, this time anti-cancer drug Xgeva.

Organizations accused of misbranding often are also accused of much worse conduct, yet very often, their cases are settled with the emphasis on the misbranding, leaving more serious allegations neither proven nor denied.  Focusing on misbranding may distract from more serious ethical, moral and legal violations.


Discussion

In the case of Amgen, the large 2012 settlement for misbranding resulted in the only guilty plea made and the largest fine paid by the company.  From my informal perusal of legal settlements made by drug, biotechnology and device companies, misbranding seems to be one of the more frequent allegations, and often the only one resulting in admissions of guilt.  It may be that it is easier to prove misbranding than other charges, and companies may admit to misbranding in settlements because the charge is not well understood by the general public and hence may carry less of a stigma than other charges, for example, kickbacks or fraud.

Yet as noted above, while misbranding seems to connote a mere technical violation, in health care misbranding can mean patients hurt by dangerous treatments that did them little if any good.  Furthermore, companies that settle allegations of or even admit to misbranding often have been charged with lots of other bad behavior, but settlements are often set up so none of these other allegations is ever confirmed or refuted.  So settlements that focus on misbranding again may nullify questions about worse ethical problems.

Now whether misbranding is itself really a transgression seems to a legal question.  But perhaps the legal challenges to misbranding as a crime ought to evoke more than just a narrow defense of the legal concept.  Of course, declaring misbranding unconstitutional could result in even weaker enforcement actions against large and powerful health care corporations,  However, maybe the inherent weakness of misbranding charges ought to inspire some rethinking of what bad behavior in health care really deserves attention.

Should not aggressive marketing of a drug as tremendously effective and safe in situations in which the drug is either minimally or not at all effective (especially in terms of improving patient-centered outcomes) or not very safe be considered possible fraud, and prosecuted as such?  Should not alleged kickbacks and bribes given to health professionals and care giving organizations be prosecuted, rather than treated as civil disputes and settled?  Should not the people who actually appeared to have committed fraud, or given bribes be prosecuted, rather than just letting their employers escape with civil monetary penalties?  Should not the leaders of big organizations on whose watches fraud and bribery allegedly occurred be charged as responsible corporate officers (look here )?

If civil authorities were willing to stop regarding big health care organizations and their leaders as "too big to jail,"  maybe less mischief would be going on in health care.  And maybe that would lead to better care for patients and better health for the public. 

ADDENDUM (21 August, 2015) - This post was republished on the Naked Capitalism blog.

12:21 PM

Promoting Amphetamines for Over-Eating - What Could Possibly Go Wrong?

Every day seems to bring the latest breathlessly touted innovation in modern health care.  The endless hawking of new health care wonders is beginning to inspire some skepticism, but maybe not enough.

The Promotion of Vyvanse for Binge Eating Disorder


For example, at the end of January, 2015, reports of the first ever drug therapy for binge eating disorder appeared.  For example, see Jonathan Rockoff writing in the Wall Street Journal

Shire PLC’s drug Vyvanse became the first drug approved for sale in the U.S. to treat some of the estimated 2.8 million adults who have a binge-eating disorder.

Rather ominously, the article described this disorder thus,

Patients regularly eat more food than they need, often when they aren’t hungry and until they feel uncomfortably full, the FDA said. The condition can lead to weight gain, obesity and related health problems.

Furthermore, it appears to be common,

An estimated 2.8 million adults in the U.S. are binge eaters, two times more than those who have the eating disorders anorexia and bulimia combined, according to Shire.

However, now there is a pharmaceutical solution!

In two pivotal studies, binge eating episodes declined to an average of one day a week among patients taking Vyvanse capsules for 12 weeks, down from an average of five days a week, Phil Vickers, Shire’s head of research and development, said in an interview.

'The approval of Vyvanse provides physicians and patients with an effective option to help curb episodes of binge eating,' Mitchell Mathis, director of the FDA’s division of psychiatry drug products, said in a statement.

Because the disease is common, that may mean a lot of money for Shire

For Shire, the approval could eventually add 'several hundred million' dollars in sales, and help the company reach its goal of $10 billion in yearly sales by 2020, said Flemming Ornskov, the company’s chief executive. Vyvanse is the company’s top-selling drug, notching $1.1 billion of the company’s $4.3 billion in total sales during the first nine months of last year.

The only hitch is that all those long suffering victims of binge eating disorder have to be found, and presented with this wonderful new alternative:

One challenge: increasing the numbers of patients diagnosed as binge eaters. Shire estimates that just 3% of Americans with the disease have been diagnosed under the mental-disorder criteria, Dr. Ornskov said.

Brief coverage of the initial approval of Vyvanse appeared in the NY Times. Bloomberg also weighed in, adding to the urgency by underlining how seriously the FDA had handled this:

'Binge eating can cause serious health problems and difficulties with work, home and social life,' Mitchell Mathis, director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

The FDA gave Vyvanse priority review, a designation for drugs with promise to 'provide a significant improvement over available therapies,' the agency said.

Among the major media covering the rollout, only Reuters noted a potential fly in the ointment in this  article,

Vyvanse is an amphetamine which, like other amphetamines, carries the potential for abuse and addiction. They also have been associated with increase blood press sure and heart rate, sudden death, stroke, heart attack, insomnia and psychiatric side effects such as hallucinations and mania.

What Really is the Clinical Evidence Supporting Vyvanse for Binge Eating Disorder?


So Vyvanse is actually lisdexamfetamine, and having been a child when the slogan "speed kills" referred to methamphetamine, not driving automobiles fast,  I thought it might be worth looking into the evidence that this somewhat new amphetamine, a relative of that infamous "speed," was now deemed a wondrous treatment for eating too much.

In particular, a recent article in JAMA Psychiatry reported results of one of the two trials Shire did of Vyvanse for binge eating disorder.(1)  The study by McElroy et al randomized patients with binge eating disorder to one of four groups, to receive the drug at dosages of 30, 50, or 70 mg/ day or placebo.  The investigators followed patients for 11 weeks.  The main outcome variable was the number of binge eating days per week reported by the patients.

Patients in all groups were binge eating during approximately 4.5 days/ week at the beginning of the study.  At 11 weeks, the average number of binge eating days/ week declined in all groups, dropping 3.3 days/ week for the placebo group, 3.5 for the 30 mg group, 4.1 for the 50 mg group, and 4.1 for the 70 mg group.  Thus, by this measure, the difference between patients given placebo versus patients given maximum dosage of the drug was an average decrease of 0.8 binge eating days a week.  That does not seem like a very big effect size, or in other words, it seems that the drug had only a small effect on binge eating compared to placebo.

That impression was reinforced by looking at some other study outcomes.  The average numbers of binge eating episodes per week at 11 weeks were 1.1 for placebo, 1.2 for the 30 mg group, 0.5 for the 50 mg group, and 0.5 for the 70 mg group.  Again, patients given the maximum dose of the drug had only a slightly smaller number of binge eating episodes than those given placebo, reinforcing the impression that the drug is not very effective.

A graph of binge eating days/ week measured over time makes things clearer.  It showed that all groups, including patients given placebo, markedly reduced their reported binge eating over the 11 week period.  Since the study did not allow any patients to get any other treatment for binge eating other than placebo or the study drug, this again suggests that the drug was not much better than placebo.  Further, the apparent reduction in binge eating by patients given placebo suggests a number of possibilities:
-  Just paying more attention to patients by putting them in a trial could lead to marked decreases in binge eating, or
-  People in binge eating trials could tend to report they are improving, whatever treatment they get, or
-  Binge eating may not be a stable phenomenon, and its intensity could vary over time, or
-  It may be difficult to make a reliable diagnosis of binge eating disorder.

In summary, at best, the trial showed that Vyvanse only caused small reductions in binge eating, and that binge eating may decrease spontaneously, or at least when patients are given more attention or scrutiny.  Thus, even putting the best face on the evidence from a trial done by the maker of Vyvanse does not greatly support the benefits of this drug.

In addition, according to evidence-based medicine advocates, the benefits of a treatment must be balanced with its potential harms.  In this study, about 5% of patients given any dosage of Vyvanse had to discontinue its use because of adverse effects.  3/196 patients initially randomized to Vyvanse had serious adverse effects, and one patient died, apparently of an amphetamine overdose.  Oddly, the article declared that the one death, due to methamphetamine overdose, was thought by a study investigator not to be related to treatment with another amphetamine, lisdexamfetamine.  That makes little sense, given that in a randomized controlled trial, the presumption is that differences in groups given different treatments were caused by these treatments.

In addition, patients given Vyvanse (lisdexamfetamine) had higher rates of various symptoms that are commonly associated with amphetamines, including insomnia, nausea, constipation or diarrhea, anxiety, feeling jittery, palpitations, and sleep disorder.

This suggests that the relatively small apparent benefits of the drug must be weighed against rates of adverse events that are not negligible, especially given the short amounts of time patients were followed. So this study did not show that the benefits of Vyvanse clearly outweigh its harms.

Finally, there were many problems with this trial that further cloud its validity, or applicability to patients (generalizability):
-  Patients were diagnosed using DSM-4 criteria, rather than the new DSM-5 criteria
-  Patients with any other psychiatric illness were excluded, limiting the applicability of its results.
-  Patients with an ostensibly chronic disease were only followed for 11 weeks, so the effects of this drug given for the treatment duration that might be needed to treat a chronic problem are unknown
-  The loss to follow-up rate, about 5% for treated patients decreases precision of the results given the relatively small effect size
-  The study was done at a large number of sites, initially 32, given the size of the patient population (starting at 260), and one site was dropped because of an "investigation," raising questions about the quality of the study implementation and data collection

So, in my humble opinion, even this Shire sponsored study, which was responsible for half the evidence used to support the approval of Vyvanse for binge eating disorder, provided only weak and questionable evidence that the benefits of the drug outweigh its harms in the short term, and no evidence about long-term use of the drug.  

However, no media coverage so far has addressed the weakness of the clinical evidence supporting the use of Vyvanse.  I have yet to see any other attempts at a rigorous, skeptical review of the clinical trial evidence supporting Vyvanse in this application.  Instead, the media reporting so far seems to have accepted the word of the manufacturer's executives, who obviously have an interest in promoting the drug.  (See the WSJ article above which just repeats assertions by a Shire executive.

Why So Much Enthusiasm about a Type of Drug with Such a Bleak Past?

This lack of skepticism was particularly baffling given the nature of the drug that was being promoted, and its long and unfortunate history.  As I noted, the amphetamines have proved to be dangerous drugs when abused, and they are abused frequently.

The beginnings of widespread amphetamine abuse grew out of previous efforts to promote these drugs for obesity (which can be, of course, a consequence of eating too much).  As documented by Cohen and colleagues(2),

The discovery of amphetamine energized the weight loss industry. Introduced as the Benzedrine inhaler in 1932 by venerable Philadelphia firm Smith, Kline, and French, the American Medical Association (AMA) soon recognized Benzedrine as a  treatment of narcolepsy, postencephaletic Parkinsonism, and certain depressive psychopathic conditions. Several clinical studies first published in the late 1930s demonstrated amphetamine’s anorectic effect. The Clark & Clark Company of Camden, NJ, established in 1941, was one of the earliest manufacturers of diet pills combining amphetamine sulfate and thyroid along with phenobarbital, aloin, and atropine sulfate to counteract untoward effects.

These rainbow pills were used with great enthusiasm, however,

adverse events, including deaths, began to be reported to the FDA as early as the 1940s. In the early 1950s, additional adverse reactions including deaths prompted a detailed investigation by the agency.

By the 1960s, the problem was acute,

Efforts had been in place at least since the 1965 Drug Abuse Control Amendments to increase accountability of the use of amphetamine in medical practice. Diversion of the drug for recreational use and the concomitant public health concerns had been recognized as a serious problem by the 1950s, but prescribing amphetamine— whether alone, as part of the rainbow regime, or for indications other than weight loss—continued to rise in the 1960s.  Under the Comprehensive Drug Abuse Prevention and Control Act of 1970, which established different schedules for certain drugs based on their medical value vis-á-vis their abuse potential, amphetamine was relegated to Schedule II. This status mandated even greater hurdles for the prescribing and dispensing of the drug as well as production ceilings. In the 1970s, FDA also reconsidered obesity as a safe and effective use of amphetamine and its congeners, ruling that amphetamines were effective but only safe for short-term use, which essentially 'marginalized the anorectics and contributed to the eventual decline in their use.'

That is, until they were resurrected as a treatment for attention deficit disorder in children, and then their use was extended to adult patients with so-called adult ADHD, and now to patients with binge eating disorder.


Given this history, the rapid approval of Vyvanse by the FDA, without the benefit of an expert panel, especially given that it was for a supposedly common disorder of adults, is very curious, and worrisome.  As Dr Daniel Carlat said (quoted on the WBUR CommonHealth blog),

 

'I’m concerned that the FDA’s approval of Vyvanse for binge eating disorder is going to worsen our problems with stimulant abuse,' Carlat says.

'Vyvanse is a derivative of Dexedrine. We’ve seen epidemics of Dexedrine abuse in the past when it was used to help people diet. I predict that the FDA has just opened the gates to another similar epidemic – after all, binge eating disorder is a subjective diagnosis that could be potentially expanded to cover many millions of people.'

Why So Much Enthusiasm about Treating Such a Doubtful Diagnosis?

As Dr Carlat noted above, it is not so obvious that binge eating disorder should be considered to be a disease.  Starting with first principles, its definition is very vague and subjective.  According to the Alliance for Eating Disorders, the DSM-5 criteria for it are:

• Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following:
  • eating, in a discrete period of time (for example, within any 2-hour period), an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances
  • a sense of lack of control over eating during the episode (for example, a feeling that one cannot stop eating or control what or how much one is eating)
• The binge-eating episodes are associated with three (or more) of the following:
  • eating much more rapidly than normal
  • eating until feeling uncomfortably full 
  • eating large amounts of food when not feeling physically hungry 
  • eating alone because of feeling embarrassed by how much one is eating
  • feeling disgusted with oneself, depressed, or very guilty afterwards
• Marked distress regarding binge eating is present.
• The binge eating occurs, on average, at least once a week for three months.
• The binge eating is not associated with the recurrent use of inappropriate compensatory behavior (for example, purging) and does not occur exclusively during the course Anorexia Nervosa, Bulimia Nervosa, or Avoidant/Restrictive Food Intake Disorder.

"An amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances?"  In this case, how are "larger," "most people," and "similar circumstances" defined, and by whom?  If I go out to eat with friends, and am the only one who has desert, or soup, for that matter, does that qualify?  Similarly subjective are "a sense of lack of control," and "eating more rapidly than normal."

In fact, the DSM-5 which ordained the new binge eating disorder diagnosis has been roundly criticized for embodying "diagnostic hyperinflation," turning aspects of the human condition, symptoms, and behavioral variants into disease.  Dr Allen Frances, who has been one of its prime critics, described "binge eating disorder" thus,

 Excessive eating 12 times in 3 months is no longer just a manifestation of gluttony and the easy availability of really great tasting food. DSM-5 has instead turned it into a psychiatric illness called Binge Eating Disorder.

Perhaps the enthusiasm to make binge eating disorder a disease had to do more with the financial relationships among the authors of DSM-5 and pharmaceutical companies that wanted to market drugs for the problem.  An article by Cosgrove and colleagues(3) noted that members of the DSM-5 work group that approved binge eating disorder as a disease included three people with financial relationships with Eli Lilly, maker of Cymbalta, three people with relationships with GlaxoSmithKline, maker of Lamictal, and one person with a relationship to Shire, maker of Vyvanse.  

Yet the discussion of Vyvanse in the big media outlets did not address these past questions about the validity of the binge eating diagnosis for which it is now being promoted. 

The Over-Marketing of Binge Eating Disorder to Promote Vyvanse

This week, however, at least some skepticism about other aspects of Vyvanse's promotion appeared in a major media outlet.  Just a few weeks after that initial coverage, the NY Times published a somewhat more skeptical take on the promotion of Vyvanse.  It noted that Shire was underwriting celebrity endorsements without disclosing its financial backing of them,

The retired tennis player Monica Seles spent this month making the rounds of television talk shows, appearing on everything from 'Good Morning America' to 'The Dr. Oz Show' to share her personal struggle with binge eating.

'It took a while until I felt comfortable talking about it,' she said in a People magazine interview, explaining that she secretly devoured food for years while she was a professional athlete. 'That’s one of the reasons I decided to do this campaign: to raise awareness that binge eating is a real medical condition.'

But that is not the only reason. Ms. Seles is a paid spokeswoman for Shire, which late last month won approval to market its top-selling drug, Vyvanse, to treat binge-eating disorder,...

Shire also was funding patient groups as part of its promotional efforts,

And patient advocacy groups — freshly infused with donations from Shire — began driving social media traffic to a company website that provides advice on how to raise the issue of binge eating with a doctor.

Furthermore, Shire has been trying to raise awareness of the new binge eating disorder diagnosis in ways that obfuscate its promotional interests,

Shire appeared to be following a familiar drug industry playbook by promoting awareness of a disorder, in this case binge eating, before more directly marketing its treatment. A company website, BingeEatingDisorder.com, makes no mention of Vyvanse but provides detailed information about how to talk about the disorder with a doctor, including a printable symptom checklist and sample opening lines to start the conversation. The site also tells patients 'don’t give up' if a doctor initially resists.

Some experts in prescription-drug abuse said the content was troubling because it appeared to coach patients about how to receive a diagnosis for a relatively uncommon condition, or shop for a new doctor if they were not successful.

Note Shire's use of undisclosed payments to celebrity spokespeople and patient advocacy groups and a disease awareness website whose connection to the company's drug was obscured suggests the operation of a stealth marketing campaign.  Furthermore, the article noted that Shire has been accused of deceptive marketing in the past, and specifically for its marketing of Vyvanse and another stimulant.

In 2011, the F.D.A. cited Shire, which is based in Dublin, for misleading advertising, and last fall the company paid $56.5 million to settle federal charges that it improperly promoted Vyvanse, Adderall and other drugs. Among the allegations, which Shire denied, was that the company played down Vyvanse’s addiction potential and said it would prevent car accidents, divorce, arrests and unemployment.

 We posted about that settlement here. 

The article also emphasized concerns about this new pushing of amphetamines,

 With the approval of Vyvanse for binge eating, 'now we have another reason for the public to learn about the glories of amphetamine — it’s very worrisome,' said Dr. Lawrence H. Diller, a behavioral pediatrician in Walnut Creek, Calif., who has written about A.D.H.D. drugs. 'My hat’s off to Shire. They’ve done it again.'

Also,

Several drug safety and addiction experts said the approval was of particular concern because of amphetamines’ troubled history as a treatment for weight loss. Vyvanse is converted by the body into an amphetamine when it is swallowed. 

From the 1940s through the 1970s, the drugs were commonly prescribed to overweight people who then became addicted. After public outcry and tighter government controls, companies stopped selling amphetamines as obesity treatments and their use is now tightly restricted. In 2012, the F.D.A. approved Qsymia, a drug combination that treats obesity and contains the amphetamine phentermine, although unlike Vyvanse, it is classified by the federal government as having a low potential for abuse.

The F.D.A. expressly forbade Shire from promoting Vyvanse as an obesity drug, but some drug safety experts said they worried its weight-loss attributes could be attractive to people who habitually overeat. The company says about 80 percent of people with the disorder are overweight or obese. Weight loss and appetite suppression are a common side effect of amphetamines.

'There’s so many reasons to be concerned about this,' said Dr. Andrew Kolodny, the chief medical officer of Phoenix House, a drug treatment organization.

He questioned why the F.D.A. approved the new use of Vyvanse so swiftly and said that given amphetamines’ troubled past, more caution was necessary.  'We had a horrible experience with amphetamines in this country, so the fact that this would just get rushed through without even bringing it before an advisory committee is especially concerning,'  he said.

However, the NY Times article still did not address the lack of good evidence that the drug provided a substantial benefit even in terms of just reducing binge eating, and questions raised whether binge eating disorder is a valid diagnosis. 

Summary

Once again we see the overenthusiastic promotion of the latest wonder drug, starting with uncritical media reports that parroted drug company executives.  At least this time some skepticism appeared about how an apparent stealth marketing campaign was organized, and about how the drug's riskiness was soft-pedaled. 

However, so far there has been little skepticism about the efficacy of the drug.  In fact, close reading of the report of one major trial showed that at best it has minimal efficacy, and even the evidence for that is weak and sketchy.  Furthermore, major news media have been hesitant to cite the real questions that have been raised about the nature of the disease for which the drug was advocated.

Most concerning is that this promotion was of an amphetamine, a type of drug with a very dark past, a type of "hard drug" responsible for major abuse problems, and known to cause particularly bad side effects, a type of drug whose illicit use has been previously sparked by over-enthusiastic marketing for dubious indications.

So once again I get to say that physicians need to be much more skeptical about the new "innovations," often promoted as miracle cures, that seem to appear weekly.  Attempts to educate physicians about clinical epidemiology, the principles of evidence based medicine, and just simply how to read a clinical research article with an appropriately skeptical and critical eye seem to have fallen by the wayside.  Furthermore, the diminishing number of health care journalists with diminishing resources may not be able to sufficiently skeptical of the marketing and public relations hype surrounding new drugs and devices.  Physicians and journalists need to have the courage to be more skeptical, and the public, who may trust journalists and physicians to cut through the bloviation, need to advocate for better training of physicians and journalists.

Finally, health care professionals and the public at large have been told to trust government regulators to only approve medicines that are safe and effective.  Yet the US Food and Drug Administration increasingly seems too cowed to challenge the pharmaceutical industry, and did not seem to exert much critical thinking before approving an amphetamine for over-eating.  The public and health care professionals ought to be advocating intensely for regulators that are less captured by the industry they are supposed to oversee.

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.

For our closing musical inspiration, or warning, note the chorus in "Amphetamine Annie" by Canned Heat...




"Speed Kills"

References

1.  McElroy SL, Hudson JI, Mitchell JE et al.  Efficacy and safety of lisdesamfetamine for treatment of adults with moderate to severe binge eating disoder: a randomized clinical trial.  JAMA Psychiatry 2015;   Link here.
2.  Cohen PA, Goday A, Swann JP. The return of rainbow diet pills.  Am J Pub Health 2012; 102: 1676-1686. Link here.

3.  Cosgrove L, Krimsky S, Wheeler EE et al.  Tripartite conflicts of interest and high stakes patent extensions in the DSM-5.  Psychother Psychosom 2014; 83: 106-113.   Link here.

11:09 AM

As the Hepatitis C Marketing Frenzy Continues, a Reminder Not to Ignore the Evidence

The Hepatitis C Spin Cycle Continues

Since our last post in July, 2014, about sofosbuvir (Sovaldi, Gilead), the $1000 pill proclaimed to be a wonder drug for the treatment of hepatitis C, the marketing juggernaut for new antiviral drugs for this condition continues to roll along.

For example, I just got a notice to look at a Gilead website which proclaims 

HCV can be cured

In October, Gilead got permission so sell Harvoni, a new combination drug that includes sofosbuvir and ledipasvir, hailed as a once daily pill that can cure hepatitis C, for a mere $94,500 for a typical treatment course. (See this article in the Wall Street Journal.) Meanwhile, AbbeVie launched its own antiviral treatment for hepatitis C, Viekira Pak, (ombitasvir, paritaprevir, and ritonavir tablets plus dasabuvir tablets) priced just under sofosbuvir, but still very expensive.  (See this Bloomberg article.)

Media coverage of these developments suggests that there is no controversy about the curative, nay lifesaving properties of these new drugs.  For example, a Wall Street Journal article about how Express Scripts will only pay for the slightly less expensive Viekira Pak referred to Sovaldi, Harvoni, and the Viekira Pak as "lifesaving medicines," and later noted, "Both Gilead’s Harvoni and AbbVie’s Viekira Pak have been shown in clinical trials to cure as many as 90% of patients..."


Never Mind the Evidence from Clinical Research, or Lack Thereof

Nearly all cases of hepatitis C can be cured, and one of the best hopes for a cure is sofosbuvir, maybe plus ledipasvir?

Never mind that the prominent published studies of sofosbuvir plus ledipasvir(1-3) did not compare this combination to any other drugs.  They simply compared different durations of treatment with the combination, plus minus other drugs.  So whether this combination is better than any other treatment, and even whether the apparently high rate of "cure," really suppression of virus detectable in blood samples at 12 weeks, would apply to patients less highly selected than those in the study was unclear. 

Of course, like every other trial of antiviral drugs for hepatitis C, these studies only assessed whether the drugs causes a "sustained virological response," that is, made the virus undetectable in patients' blood for 12 weeks.  They did not assess whether the virus reappeared after that, and certainly did not assess whether the drugs affected the development of the dreaded complications of hepatitis C infection, that is cirrhosis, liver failure, liver cancer, and death.  In the absence of controlled trials that assessed these long term clinical outcomes, the assertions that these drugs are curative or lifesaving do not appear to be well substantiated.

It is not even obvious that the new sofosbuvir based regimens are better than the old peg-interferon based regimens.   As we noted here, there apparently has only been one published study that compared sofosbuvir to another antiviral drug, peg-interferon.  That study had multiple methodologic problems, most of which appeared likely to make sofosbuvir look better, but nonetheless did not show sofosbuvir to be clearly more effective or safer than this, or any other alternative. (See posts here and here.)

In October, a cost-effectiveness analysis appeared that was used to make the case that expensive drugs like sofosbuvir could nevertheless be cost-effective.(4)  It showed that the drugs increased quality adjusted life expectancy for a relatively modest cost.

Never mind that the analysis was based on the highly questionable assumption, that "treatment resulting in cure [presumably meaning sustained virological response] could leave patients with residual fibrosis consistent with their stage at the time but without additional progression." [Italics added.] This assumption was completely unsupported by randomized controlled trial data.  As Chavez-Tapia et al wrote in a December, 2014, letter to JAMA,(5) "SVR is poorly correalted with clinical outcomes in randomized controlled trials, and even though efforts have been made to correlate it with mortality, evidence to date is insufficient to assert that SVR will translate into improved quality of life or life expectancy."

Is the evidence supporting the Viekira Pak any better?

Not obviously.  The prominent November, 2014, New England Journal of Medicine study by Ferenci et al of the drugs within the Viekira Pak also equated 12 week SVR with cure, also failed to allow patients long-term, and also failed to assess clinically important complications of hepatitis C such as cirrhosis, liver failure, liver cancer, and death.  Furthermore, the study did not compare the Viekira Pak with any other treatment option, e.g., one containing sofosbuvir or peg-interferon, or to placebo.(6)   Thus, assertions that the Viekira Pak is curative or lifesaving also do not appear to be substantiated by evidence from well-designed long-term clinical trials.

However, the lack of evidence so far as not discouraged the breathless claims, and the acceptance of these claims in the media, and probably by many physicians.

Another Skeptical Review

However, one bit of common sense about all this just appeared in the form of a 2015 article in the French journal Prescrire International.(7)  The full article requires a subscription, but a summary is available on the web, and includes the following dry but telling language:

Sofosbuvir’s initial clinical evaluation includes several comparative trials. But these trials investigate its harm-benefit balance in a minimal way. Sofosbuvir has not been compared directly with a viral protease inhibitor in a randomised clinical trial. The evaluation of sofosbuvir in patients infected with a genotype 1 HCV and suffering from cirrhosis is very poor.

Clinical trials have shown that the addition of sofosbuvir to various drug combinations increases their virological efficacy, but there is no guarantee of success.

In practice, in patients with liver damage requiring antiviral drug therapy, sofosbuvir seems to be at least as effective and less harmful than viral protease inhibitors such as boceprevir. Its use makes it possible to reduce the duration of treatment by several months. But there is a great deal of uncertainty as to its adverse effects and its interactions. In genotype 1 cases, the addition of sofosbuvir to the peginterferon alfa + ribavirine combination is an option. In genotype 2 or 3 cases, sofosbuvir is an alternative to peginterferon alfa. However, given the slow progress of hepatitis C and the many unknowns surrounding sofosbuvir, it is a reasonable option to await further clinical evidence to be available.

Meanwhile, more skepticism about the sky high pricing of these new antiviral drugs appeared in the form of a lawsuit by the Southeastern Pennsylvania Transportation Authority (SEPTA) for price gouging that allegedly violates antitrust laws.

But even the coverage of this lawsuit, like nearly all the other coverage of Sovaldi, Harvoni, and competing drugs, assumed that these drugs are miracle cures, e.g., see this Wall Street Journal article.  As we discussed in detail before (look here, here, here, here, here and here)  there is no good evidence that any of these new treatments prevents cirrhosis, liver failure, liver cancer, or death due to hepatitis C, and their long-term safety is unclear.  Similar points have been made by rigorous reviews in Germany, in the US, and now in France.  Yet the antiviral spin continues without regard to evidence, or the lack thereof, from good clinical research.  I would like to hope that each new added bit of skepticism, now including the Prescrire International review, will have some effect.  But that may be wishful thinking, since most of what goes on in the health care "industry" now seems less than fully reality based.

Summary

As we said before,  the Sovaldi (and now Harvoni, Viekira Pak, etc) 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 likely not buy us the promised miracles and triumphs.

It is disappointing that so many physicians and other health professionals have been caught up in this hype and spin, probably abetted by their wishful thinking about cures of hepatitis C, and perhaps also abetted by financial conflicts of interest.  Yet to protect the best interests of their patients, they should be rigorously skeptical of illogical or evidence-free arguments made to further vested financial interests.

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.

References

1.  Afdhal N, Reddy KR, Nelson DR et al.  Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.  N Engl J Med 2014; 370: 1483-98.  Link here.
2.  Afdhal N, Zeuzern S, Kwo P et al.  Lepipasvir and sofosbuvir for untreated HCV genotype 1 infection.  N Engl J Med 2014; 370: 1889-98.  Link here.
3.  Kowdley KV, Gordon SC, Reddy KR et al.  Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.  N Engl J Med 2014; 370: 1879 - 1888.  Link here.
4.  Liu S, Watcha A, Holodniy M et al.  Sofosbuvir-based treatment regimens for chronic genotype 1 hepatitis C virus infection in the U.S. incarcerated populations: a cost-effectiveness analysis.  Ann Intern Med 2014; 161: 546 - 553.  Link here.
5.  Chavez-Tapia NC, Barrientos-Gutierrez TB, Uribe M. Assessment of outcomes of hepatitis C treatment.  JAMA 2014; 312: 2570-2571.  Link here. 
6.  Ferenci P, Bernstein D, Lalezari J et al. ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV. N Engl J Med 2014; 370:1983-1992. Link here.  
7.  Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete.  Prescrire Int 2015; 24: 5- 10.  Link here.

8:40 AM

Even Crazy Eddie Knows "Corporations Don't Commit Crimes, People Commit Crimes" - But Biotronik Settles

The deals the government gives are INSANE!!!  Just ask Crazy Eddie's former Chief Financial Officer.

The Former Crazy Eddie CFO on Impunity

Those of a certain age who were in or near the New York area remember Crazy Eddie, a discount appliance and electronics retailer with insane advertisements.




As reported by CNN, Sam F Antar, the former Chief Financial Officer of Crazy Eddie, was a speaker on a conference on financial fraud,

The U.S. government is losing the war against white collar crime.

That's the message from Sam E. Antar, one of the masterminds of the massive Crazy Eddie fraud of the 1980s.

'We are in the golden era of white-collar crime. My biggest regret is I should've been a criminal today rather than 20 years ago,' Antar told CNNMoney on the sidelines of a New Jersey securities fraud summit.

Antar drew a big round of applause when he pointed out that no one from Wall Street went to prison because of crimes that led to the financial crisis.

'We are devoting far less resources to combating crooks like myself today than back in my day,' he said.

Antar knows a thing or two about corporate fraud. He served as Chief Financial Officer of Crazy Eddie, the electronics retailer that became one of the symbols of white-collar crime in the 1980s.

Known for its loud commercials promising "INSAAAANE" prices, Crazy Eddie got into trouble for understating income to avoid taxes and then committing securities fraud once it decided to go public.

'Crazy Eddie was from Day One planned to be a criminal enterprise. We committed our crimes simply because we could,' said Antar, whose cousin Eddie Antar founded the chain.

Because he 'showed the feds where the bodies were buried,' Antar got off with only six months of house arrest, community service and tens of thousands of dollars in civil penalties. Crazy Eddie co-founder Eddie Antar served more than six years in prison.

Today, the convicted felon is advising the government and private companies about white-collar crime. Antar expressed frustration with the government's failure to put Wall Street bankers behind bars.

'We have turned prosecutors into tax collectors,' he said. 'Corporations don't commit crimes, people commit crimes.'

While the focus of this conference was corporate fraud and crime in the financial sector, we have frequently discussed corporate crime and corruption in the health care sector.  We have noted, especially in our posts on the march of legal settlements, that most wrongdoing by big health care organizations is punished - if it is punished at all - only by fines assessed against the organization, and perhaps a lightly enforced corporate integrity or deferred prosecution agreement.  Rarely does the organization admit wrongdoing.  Rarely are criminal charges involved (the settlements are usually civil).  Almost never do any individuals who authorized, directed or planned the wrongdoing suffer any negative consequences.

However, in health care, corporations do not do wrong.  People do wrong.

This brings us to our latest example.


Biotronik Settles Kickback Allegations for $4.9 Million

This story barely rippled the media waters, getting its most extensive coverage in the (Portland) Oregonian.

Biotronik, Inc, the Lake Oswego medical device manufacturing firm, will pay $4.9 million to the federal government to resolve allegations that the firm paid kickbacks to doctors in Nevada and Arizona to use its products.

In particular, the Department of Justice charged,

The settlement resolves allegations that Biotronik, through the payment of kickbacks to physicians, caused hospitals and ambulatory surgery centers to submit false claims to Medicare and Medicaid for the implantation of Biotronik pacemakers, defibrillators and cardiac resynchronization therapy devices.

Biotronik allegedly induced electrophysiologists and cardiologists practicing in Nevada and Arizona to continue using Biotronik devices, or to convert to Biotronik devices, by paying the implanting physician in the form of repeated meals at expensive restaurants and inflated payments for membership on a physician advisory board.

So the issue was not only defrauding the government, but giving kickbacks to doctors to induce them to use Biotronik devices, presumably whether or not such devices were the best treatments for their individual patients. Thus, the alleged conduct could have resulted in the unnecessary or inappropriate implantation of devices, leading to patient risks in the absence of benefits.

Nonetheless, as is usual in such cases, Biotronik did not admit any guilt, and in fact refused to talk to the reporter.  Furthermore, no one at Biotronik who authorized, directed or implemented the conduct in question suffered any negative consequence.

The light touch of the law on Biotronik was striking considering the company's track record.

Biotronik's Track Record: 2011 - 2013

Physicians Settle Allegations They Concealed Payments from Biotronik

In fact, the 2014 settlement was actually the second settlement resulting from allegations that Biotronik paid physicians to get them to use its devices.  As the Oregonian reported in 2013,

The state recently concluded a court case against two Salem doctors who put heart implants into patients without telling them that a manufacturer's training program put a sales representative into the operating room. The [Oregon] DOJ accused the doctors in the civil case of having 'misrepresented' their services as 'for the exclusive benefit of the patient' and 'concealing' from patients payments that created a potential "incentive" to use Biotronik implants -- defibrillators and pacemakers. The surgeons received between $400 and $1,250 for implant surgeries when a trainee was present.

This case was unusual in that the prosecutors, from the state of Oregon here, not the US Department of Justice, targeted the physicians who received the money rather than the corporation that provided it. So these individuals actually suffered some negative consequences, albeit rather minor,

cardiologists Matthew Fedor and Kyong Turk admitted no wrongdoing but agreed to pay $25,000 each and inform future patients of any payments from a drug or device maker in connection with their services to that patient and when admitting sales representative trainees to the operating room.

At the time,

At Biotronik's U.S. headquarters in Lake Oswego, president Jake Langer called the state's case unfair and detrimental to good health care.

'We are really clean when it comes to our relationships with physicians,' he said. He blamed the first-of-its-kind case on overzealous prosecutors trying 'to set up a new law' without going to the Legislature.

In 2011, Documents Revealed Biotronik's Marketing Tactics

Furthermore, the relatively meager penalties provided for by the 2014 and 2013 settlements were more incongruous given the colorful evidence provided by a disgruntled Biotronik employee reported in a 2011 New York Times article, about which we posted here.  The article suggested that Biotronik attempted to boost sales through "seeding trials," which are more about recruiting doctors than clinical research, paying "consulting fees" to doctors who wanted their patients implanted with Biotronik products, and  who actually implanted such products, and finally currying physicians' favor by hiring their spouses.

Summary

Those government settlements really are INSAAANE.


The Biotronik settlements followed a familiar pattern.  Now that we have been following organizational misbehavior in health care for some years, we see that organizations that get into trouble once are very likely to get into trouble again.

This may be enabled by how government regulators and law enforcement give large health care organizations such  gentle treatment.  We have talked about the march of legal settlements by such organizations before.  Allegations are usually resolved with legal settlements that involve no admissions of guilt, small monetary penalties (compared with these organizations' total revenues), and sometimes apparently toothless corporate integrity agreements.  Settlements get desultory public notice, rarely informed by previous settlements or other evidence of previous misbehavior.  No individual who may have authorized, encouraged, directed, or implemented the bad behavior is likely to suffer any negative consequences.   It does not help that while nominally public, these settlements get little press, and what coverage there is usually fails to put the whole pattern together.

So we would urge the reporters who cover the next settlements by big health care organizations at least look to see if the organizations had been involved in similar settlements in the past.

Furthermore, as we have said all to often,...   The failure of the current limp legal efforts against such corruption is evident by how many corporations have become ethical repeat offenders.  Pervasive bad behavior by large health care organizations has got to be a major cause of our ongoing health care dysfunction.  So, to really deter bad behavior, those who authorized, directed or implemented bad behavior must be held accountable. As long as they are not, expect the bad behavior to continue.

1:02 PM

Promises, Promises - Dendreon Bankrupt, Steward Healthcare Closes Quincy Hospital

Physicians and other health professionals are trained to attempt to make realistic, unbiased predictions, most frequently of the prognoses of individual patients.  Thus physicians may not question apparently authoritative predictions, claims, and promises made in the health care context.  They may not question, for example, predictions about the efficacy and safety of drugs and devices, even by people working for drug and device companies; predictions of the benefits of health care services, even by people working for the hospitals that provide them; and predictions of the benefits of health policies, even by politicians or organizations that stand to benefit if they are adapted.  Yet such predictions may influence health care policies and decisions.

However, in the business culture, confidence is often conflated with competence.  Generic managers, trained in business schools, and steeped in business culture, now run most health care organizations.  Managers are responsible for most of the sorts of predictions listed above, perhaps mediated through their marketing and public relations staffs.


Thus it should come as no surprise that a lot of the predictions, claims, and promises we now hear in health care eventually come to naught, but long after they have already influenced decisions and policy. 

Dendreon Bankruptcy

In 2007, we first wrote about biotechnology company Dendreon, and its single product, a vaccine meant to treat prostate cancer with the trade name Provenge ( generic name, sipuleucel-T).  Provenge has aroused unusual passions.  When the US Food and Drug Administration delayed its approval after a single small trial showed equivocal results, much hoopla produced by Dendreon partisans occurred.  Investors and patient advocates protested, at times picketing the FDA.  Someone threatened physicians who were publicly skeptical of the vaccine.  It did appear that Dendreon funded a patient advocacy group which was one of the vaccine's vocal supporters.

In 2009, Matthew Herper, writing in Forbes, reported that the company had released preliminary data from a new trial before the results were presented at any conference or published, apparently after breaking the treatment blinding, causing one biostatistics expert to say, "I'm shocked."  At that point, company CEO Mitch Gold

has been using the [controversial, unpublished] data to talk up Provenge. 'We’re clearly within shooting range,' Gold told analysts at a JP Morgan investor conference in January. 'Sometimes I use a football analogy where we are on the 10-yard line and we are in the red zone, and we need to punch it in the end zone right now.'

A TheStreet.com article noted that

Dendreon threw a celebratory cocktail party Tuesday night at a Chicago hotel just off the Miracle Mile. CEO Mitch Gold was beaming as he slapped backs, shook hands and hugged employees, investors and supporters.

In 2010, the FDA approved the vaccine based on the eventually published study that showed that Provenge prolonged survival for an average of about four months.  The company then priced a course of therapy at $93,000, starting one of the early big controversies about extremely expensive new drugs with apparently small benefits  (see this Washington Post article) .  

According to a 2011 article by Jim Edwards for CBS, through 2010 and into 2011, CEO Gold and Chief Operating Officer Hans Bishop continued to make optimistic forecasts about sales of Provenge.  But during the same time period, Gold and other insiders sold $87 million in stock.  Then in 2011, the company announced that its revenue projections had been far too optimistic.

Things continued downhill from there.  Dendreon settled for $40 million an investor class action lawsuit that asserted corporate executives made "false or misleading statements about the company," according to one very brief story in the Seattle Times.  

Then, on November 10, 2014, per the Seattle Times, the company announced it would file for bankruptcy,

Dendreon said it has filed for bankruptcy protection as part of a plan to restructure $620 million in debt, a move likely to effectively wipe out the value of its common stock.

The biotechnology company, once Seattle’s largest, filed a voluntary Chapter 11 bankruptcy petition Monday in Delaware.

"Within shooting range" - no more.  Yet from 2007 to 2011, the company CEO (and COO), aided by corporate marketers and public relations, created a huge brouhaha over the company's one product, making management insiders rich meanwhile.  The high price the company charged for the vaccine may have driven up the stock price early, facilitating the amassing of wealth by top management insiders.  While this pricing decision may have helped other health care corporations pursue gigantic revenues from new products, it may have ultimately damped demand and lead to bankruptcy.  How much money the managers who created the hoopla will keep remains to be seen.  Why skepticism about the executives fabulous predictions was not initially higher is unclear. 

ADDENDUM (20 November, 2014) - Added paragraph re 2013 investor class action settlement.

Steward Healthcare Closes Quincy Hospital

Starting in 2010, we wrote about the takeover of the Massachusetts non-profit Catholic hospital system Caritas Christi by private equity firm Cerberus Capital Management (named for the mythological three-headed dog that guards the gates of the underworld, look here.)  Despite some controversy, and the apparent contrast between Catholicism and the three-headed dog guarding the gates of hell, the takeover was approved, yielding the now privately held, for-profit Steward Healthcare.

Over the time period, proponents of the sale gave some big assurances.  In 2010, the Boston Globe reported,

Brett Ingersoll, co-head of private equity at Cerberus, called the Caritas acquisition 'a big win for the hard-working communities of Greater Boston.'’ Ingersoll said the new owners 'plan to create jobs, expand local tax bases, and provide world-class health care facilities.'

Similarly, from a Boston Herald article,

'Cerberus is pleased to be making a long-term investment that will help ensure the viability and future success of the Caritas Christi health care system,' said W. Brett Ingersoll, co-director of private equity at Cerberus in a statement.  'Caritas is the region's largest community hospital network, and our investment will give physicians, nurses, and other health professionals the additional tools they need to deliver world-class care to patients in the communities they serve.'

Later in October, Dr Ralph De La Torre, Caritas Christi CEO, a former cardiovascular surgeon who apparently no longer held an active medical license (look here), intoned per the Globe,

'The business plan, the strategy, or whatever you want to call it, is all about keeping care locally,' he said. 'If we improve the facilities, improve the infrastructure, make it so that our very own patients want to stay in our hospitals, that’s the business plan.'

Furthermore, at the same meeting,

The new holding company 'will continue to promote the public interest after this transaction,' Lisa Gray, Cerberus general counsel executive and a Steward board member, told the council.

A few days later, again per the Globe, Caritas Christi spokesman Chris Murphy said,

Once finalized, the sale will ensure the future of our system, the jobs of our employees, and the pensions of our retirees.

The takeover was eventually completed, and the new Steward Healthcare commenced acquisitions of other hospitals.  CEO De La Torre had become the most highly paid hospital system CEO in the Boston area, and was widely anticipated to be on the way to even higher compensation under Steward (look here). 

In 2011, Steward set its sights on Quincy Medical Center.  Once again, promises were made, per the Boston Herald,

In a statement today, interim CEO John Kastanis said the hospital's announcement is 'the culmination of an exhaustive process to find a capital partner who is committed to our mission, our employees and physicians, and the communities we serve.'

'We have found the partner in Steward,' Katsanis said.  'Steward is a community-based hospital system with tremendous resources that will enable us to grow and continue to provide world-class health care for generations to come.'

The Massachusetts Attorney General approved the sale of Quincy Medical Center to Steward, but with some conditions, as a September 8, 2011, Boston Globe article noted,

[Attorney General Martha]  Coakley imposed multiple conditions on the deal that are meant to safeguard patients and employees of the financially struggling hospitals. They included a guarantee that Boston-based Steward will not sell either one for at least five years, that it will keep making capital improvements after five years,...

Also, Steward

agreed to a 10-year “no close’’ period for both hospitals, though the deals included clauses that would allow Steward to close the hospitals under certain conditions in the last three years if financial targets aren’t met.

It all sounded so good.  However, on November 6, 2014, slightly more than three years after the sale of Quincy Medical Center was approved with the conditions above, per the Globe,

Steward Health Care System said Thursday that it would close Quincy Medical Center and displace nearly 700 workers after the long-struggling hospital finally succumbed to the intense competition for patients south of Boston.

 The shutdown, scheduled to be completed by the end the year, marks the biggest hospital closing in the state in at least a decade and the first failure for Steward, the for-profit company that promised to reinvent community health care when it entered the Massachusetts market four years ago.

So what happened to "world class health care for generations to come," or being "committed to our employees?"  The commitment lasted a little over three years, the employees will need to find new jobs, and the patients will need to go elsewhere for health care, whether world class or not.  At least Attorney General Coakley is looking into options given that Steward Health Care seemed to have violated that 2011 agreement, per the Herald,

The Attorney General’s Office is investigating whether Steward Health Care System violated the terms of a 2011 agreement when it announced yesterday that Quincy Medical Center will shut down operations by the end of the year, a spokesman said.

'We have just been notified about this decision and are currently reviewing it in the context of Steward’s legal obligations,' said Brad Puffer, a spokesman for Attorney General Martha Coakley.
When Steward bought the 196-bed Quincy hospital in a bankruptcy auction in 2011, it signed an agreement with Coakley that included a 10-year 'No Close Period' requiring that it 'maintain an acute care hospital in Quincy providing at least the same scope of services as Quincy Medical Center currently provides.'

Steward could close Quincy Medical in the last three-and-a-half years of that 10-year period if it could show the hospital 'experienced two consecutive fiscal years of negative operating margins' and provide the state’s Department of Public Health with 'at least 18 months prior written notice of its intent to close,' according to the agreement.

A Steward spokeswoman declined to comment when asked about the no-close clause last night.

 In any case, while there was plenty of skepticism about the acquisition of Caritas Christi by Cerberus Capital Management, and the ambitious expansion plans of the resulting Steward Healthcare, it was insufficient to slow down these aggressive plans.  I could speculate that had more skepticism come from physicians and health care policy experts, maybe things would have been different.  It is likely that Steward Healthcare/ Cerberus Capital Management insiders made plenty of money from the deals, although now that the hospital system is privately held, little about individual compensation has been disclosed.  The takeover of a once religious based, non-profit health care system by private equity, and the aggressive initial expansion of the new for-profit system, were in part enabled by extravagant promises and claims.  While this expansion is now clearly seen as not an unalloyed good, those making the claims likely have already personally profited from it. 

Summary

There have been lots of other expansive predictions in our era of commercialized health care that have come to naught.  In general, lots of physicians seemed convinced by predictions that:
- commercial managed care would improve access and quality, and cut costs
- large, vertically integrated hospital systems would improve access and quality, and cut costs
- commercial electronic health records would - guest what - improve access and quality, and cut costs.

How did those turn out?

There were lots of more specific and local predictions that proved equally inoperative.  Remember the former CEO of the Allegheny Health Education and Research Foundation (AHERF), one of the first really large vertically integrated health care systems, promising to create a more flexible, adoptable, and agile organization.  That organization was soon bankrupt, and he was soon in jail.  (Look here).

So now we have two new reminders that even apparently authoritative health care claims, predictions, and promises, particularly when made by executives or managers, when enabled through public relations or marketing, or appear likely to be self-serving, ought to be regarded with extreme skepticism, if not outright ridicule.  Many doctors now realize that they should not trust advertising of health care products and services.  Nor should they trust flowery pronouncements of business people about health care products, services, and policies when the predictors are in a position to benefit from short term actions adherent to these predictions.

True health care reform would restore leadership of health care that is knowledgeable about health care, committed to its values, and held accountable for patients' and the public's health.  Meanwhile, we ought to be extremely skeptical of claims, predictions, and promises made by health care organizations' management. 

8:44 AM