Thursday, September 18, 2014

Value Extractors, "Super-Managers," Vampires and the Decline of the US and US Health Care

Appearing during the last few weeks were a series of articles that tied the decline of the US economy to huge systemic problems with leadership and governance of large organizations.  While the articles were not focused on health care, they included some health care relevant examples, and were clearly applicable to health care as part of the larger political, social, and economic system.  The articles reiterated concerns we have expressed, about leadership of health care by generic managers, perverse executive compensation, the financialization of health care, in part enabled by regulatory capture, and the abandonment by effective stewardship by boards of directors, but with new takes on them.

The articles included "Profits Without Prosperity," by William Lazonick in the the Harvard Business Review,  "Why Have US Companies Become Such Skinflints," by Paul Roberts in the Los Angeles Times, and "How Business Leaders Turned Into Vampires," by Steve Denning in Forbes, which in turn was partially based on "The Rise (and Likely Fall) of the Talent Economy," in the Harvard Business Review.

Let me summarize the main points, and discuss some health care examples.

"Super-Managers" as Value Extractors

Steve Denning's article contrasted people who  add value to the economy versus those who extract value.  The first species of value extractor he listed was:

 ‘Super-managers’ are people who hold administrative positions in the C-suite of private-sector bureaucracies but are masquerading as entrepreneurs. They are, to use Thomas Piketty’s slyly ironic term, “super-managers.” As such, they have been able to extract extraordinary levels of compensation. They have been lavished with stock and stock options and have been able to 'manage' the share price of their firms with massive share buybacks and other financial engineering so that they receive massive bonuses. As Bill Lazonick documented in the September 2014 issue of HBR, the net effect of their activities is to extract value, rather than create value [see below]. 

Presumably, "super-managers" as health care executives are also likely to be generic managers, unlikely to have much actual knowledge of caring for patients, unsympathetic to the values of health care professionals, and hence unlikely to uphold the health care mission.

He noted that

 there is a tendency to dismiss the activities of ‘vampire talent’ as de minimis. 'That’s capitalism, right? Every man for himself. It’s no big deal if there’s an occasional bad apple in the barrel. The ‘invisible hand’ of capitalism will make everything come out right for society in the end.'

However,

 The problem today is that the super-sized executive compensation, the gambling and the toll-keeping of the financial sector aren’t tiny sideshows. They have grown exponentially and are now macro-economic in scale. They have become almost the main game of the financial sector and the main driver of executive behavior in big business. When money becomes the end, not the means, then the result is what analyst Gautam Mukunda calls 'excessive financialization' of the economy, in his article, 'The Price of Wall Street Power,' in the June 2014 issue of Harvard Business Review.

Mr Denning further asserted that the value extraction of super-managers is augmented by the value extraction of two different groups of players, hedge funds that speculate with other peoples' money, and "tollkeepers" who extract rents through the financial system.  

Furthermore, Mr Denning stated that

 The growth of super-sized executive compensation is inversely related to performance. The super-managers are in effect being rewarded for doing the wrong thing.
Of course, if executives in health care, like those in other sectors, are mainly concerned with enriching themselves in the short-term, than they are not mainly concerned with patients' and the public's health, or the values of health care professionals, and hence the performance of their organizations in terms of health care processes and outcomes will suffer. 

Furthermore, the ability of commercial health care firms to actually make a positive impact on health care will be decreased as they are whipsawed by other value extractors like hedge funds and tollkeepers. 

Example - Renaissance Technologies

Mr Denning's first example of tollkeepers' value extraction was:

James Simons, the founder of Renaissance Technologies, ranks fourth on Institutional Investor’s Alpha list of top hedge fund earners for 2013, with $2.2 billion in compensation. He consistently earns at that level by using sophisticated algorithms and servers hardwired to the NYSE servers to take advantage of tiny arbitrage opportunities faster than anybody else. For Renaissance, five minutes is a long holding period for a share.

In fact, as we noted here, Renaissance Technologies does not hesitate in trading health care firms.  Furthermore, that company has a noteworthy direct tie to health care.  Its current co-CEO, Peter F Brown, is married to the current Commissioner of the US Food and Drug Administration (FDA).

Value Extraction and Share Buybacks

William Lazonick's article also emphasized how corporate leadership is now focused on extracting value from their companies for their own personal benefit, rather than promoting growth, innovation, better products and services, etc.  In particular, large public for-profit companies now tend to use their surplus capital to buy back shares of their own stock, rather than invest in new facilities, equipment, employees, etc.  Perhaps we should not be surprised that this was facilitated by changes in US government regulation, that is deregulation, in this case instituted during the Reagan administration:

Companies have been allowed to repurchase their shares on the open market with virtually no regulatory limits since 1982, when the SEC instituted Rule 10b - 18 of the Securities Exchange Act.

Note that

The rule was a major departure from the agency's original mandate, laid out in the Securities Exchange Act of 1934.  The act was a reaction to a host of unscrupulous activities that had fueled speculation in the Roaring '20's, leading to the stock market crash of 1929 and the Great Depression.

Given the context, and that the deregulation was implemented by an SEC chair who was "the first Wall Street insider to lead the commission," this seems to be an example of regulatory capture in service of corporate insiders.

The issue here is that while it might make some financial sense for companies to buy back their own shares if they are priced at bargain rates, after this change they could buy shares at any price without supervision.  On one hand, such purchases could lead to short-term bumps in stock prices. On the other hand, a major reason for these buybacks appears to be that they enrich corporate insiders, particularly top hired executives, who now receive much of their pay in the form of stock and stock options, and often can get bonuses based on short-term increases in stock prices.  Lazonick wrote,

Combined with pressure from Wall Street, stock-based incentives make senior executives extremely motivated to do buybacks on a colossal and systemic scale.

Consider the 10 largest repurchasers, which spent a combined $859 billion on buybacks, an amount equal to 68% of their combined net income, from 2003 through 2012. (See the exhibit “The Top 10 Stock Repurchasers.”) During the same decade, their CEOs received, on average, a total of $168 million each in compensation. On average, 34% of their compensation was in the form of stock options and 24% in stock awards. At these companies the next four highest-paid senior executives each received, on average, $77 million in compensation during the 10 years—27% of it in stock options and 29% in stock awards. Yet since 2003 only three of the 10 largest repurchasers—Exxon Mobil, IBM, and Procter & Gamble—have outperformed the S&P 500 Index.

Example - Pfizer

Mr Lazonick's noted some potential outcomes of the frenzy of stock buybacks affecting the US pharmaceutical industry and hence the US health care system.

In response to complaints that U.S. drug prices are at least twice those in any other country, Pfizer and other U.S. pharmaceutical companies have argued that the profits from these high prices—enabled by a generous intellectual-property regime and lax price regulation— permit more R&D to be done in the United States than elsewhere. Yet from 2003 through 2012, Pfizer funneled an amount equal to 71% of its profits into buybacks, and an amount equal to 75% of its profits into dividends. In other words, it spent more on buybacks and dividends than it earned and tapped its capital reserves to help fund them. The reality is, Americans pay high drug prices so that major pharmaceutical companies can boost their stock prices and pad executive pay.

Moreover, during approximately the same period Pfizer compiled an amazing record of legal misadventures including settlements of allegations of unethical behavior, and some convictions, including one for being a racketeering influenced corrupt organization (RICO), as most recently reviewed here, and then updated here.  So while it was putting huge amounts into buybacks, it also put billions into legal fines and costs. This suggests that note only does executive compensation not correlate with "performance," it may also correlate with corporate bad behavior.

The "Shareholder Value" Dogma

In explaining how US corporate executives turned to stock buybacks to boost their own pay, at the expense of essentially everyone else, Mr Lazonick sounded some familiar themes.  One was focus on short-term revenues and short-term stock performance drive by the "share-holder value" dogma out of business schools,

the notion that the CEO's main obligation is to shareholders. It's based on a misconception of the shareholders' role in the modem corporation. The philosophical justification for giving them all excess corporate profits is that they are best positioned to allocate resources because they have the most interest in ensuring that capital generates the highest returns. This proposition is central to the 'maximizing shareholder value" (MSV) arguments espoused over the years, most notably by Michael C. Jensen. The MSV school also posits that companies' so-called free cash flow should be distributed to shareholders because only they make investments without a guaranteed return -- and hence bear risk.

But the MSV school ignores other participants in the economy who bear risk by investing without a guaranteed return. Taxpayers take on such risk through government agencies that invest in infrastructure and knowledge creation. And workers take it on by investing in the development of their capabilities at the firms that employ them. As risk bearers, taxpayers, whose dollars support business enterprises, and workers, whose efforts generate productivity improvements, have claims on profits that are at least as strong as the shareholders'.

Mr Denning similarly noted

The intellectual foundation of all this behavior is the notion that the purpose of a firm is to maximize shareholder value. Unless we do something about this intellectual foundation, the problem will remain. Changes in a few regulations or the tax code won’t make much difference. ‘Vampire talent’ will find ways around them.

Nor will change happen merely by pointing out that shareholder primacy is a very bad idea. Bad ideas don’t die just because they are bad. They hang around until a consensus forms around another idea that is better.


Mr Roberts' article "Why Have US Companies Become Such Skinflints," went at this issue from a slightly different angle, noting first


The bigger story here is what might be called the Great Narrowing of the Corporate Mind: the growing willingness by business to pursue an agenda separate from, and even entirely at odds with, the broader goals of society.

He attributed this to the notion promulgated by

conservative economists, [that] the best way for companies to help society was to ditch the idea of corporate social obligation and let business do what business does best: maximize profits.

He noted that this focus on short-term revenues has led to the decline in long-term results,

 But because management is so focused on share price and because share price depends heavily on current company earnings, strategic focus has grown ever more short term: do whatever is needed to hit next quarter's earnings target. And since cost-cutting is a quick way to boost near-term earnings, layoffs and other downsizing once regarded as emergency measures are now routine.

And here is the paradox. Companies are so obsessed with short-term performance that they are undermining their long-term self-interest. Employees have been demoralized by constant cutbacks. Investment in equipment upgrades, worker training and research — all essential to long-term profitability and competitiveness — is falling.

Of course, this is antithetical to the "innovation" that current corporate boosters proclaim as the goal of drug, biotechnology, medical device companies and other players in the brave new world of corporate health care.  


The Incestuous Mechanisms Used to Set Executive Compensation

Another explanation for the rise in value extraction, and specifically the use of share buybacks to reward top corporate hired executives, was the incestuous way in which corporations set pay for top hired executives. Mr Lazonick wrote,

Many studies have shown that large companies tend to use the same set of consultants to benchmark executive compensation, and that each consultant recommends that the client pay its CEO well above average. As a result, compensation inevitably ratchets up over time. The studies also show that even declines in stock price increase executive pay: When a company's stock price falls, the board stuffs even more options and stock awards into top executives' packages, claiming that it must ensure that they won't jump ship and will do whatever is necessary to get the stock price back up.

This is enabled by boards of directors who seem to represent the 'CEO union,' not stockholders, and certainly not other less favored employees, customers, clients or patients, or society at large,

Boards are currently dominated by other CEOs, who have a strong bias toward ratifying higher pay packages for their peers. When approving enormous distributions to shareholders and stock-based pay for top executives, these directors believe they're acting in the interests of shareholders.

Once again, this was also enabled by the dergulation that started with during the Reagan administration, and continues this day (although the specific relevant deregulatory change occurred during the Clinton administration),

 In 1991 the SEC began allowing top executives to keep the gains from immediately selling stock acquired from options. Previously, they had to hold the stock for six months or give up any 'short-swing' gains. That decision has only served to reinforce top executives' overriding personal interest in boosting stock prices. And because corporations aren't required to disclose daily buyback activity, it gives executives the opportunity to trade, undetected, on inside information about when buybacks are being done. 

Summary

Note that while all the discussion above has been about for-profit corporations, we have seen that in health care, various non-profit organizations, particularly hospitals, hospital systems, academic medical institutions, and health insurers, which all now operate in the current market fundamentalist environment, are acting more and more like for-profits.  So while non-profit corporate executives cannot do stock buybacks, they are also all too often generic managers, given huge compensation, but not often for upholding the mission, putting patients' and the public's health first, or upholding health care professionals' values.  

It is striking that we are beginning to see protests like those above not in radical publications, but in the Harvard Business Review and Forbes.  It is more striking that these protestors are beginning to fear the worst.  Mr Roberts wrote,

Sooner or later, markets punish such myopic behavior. Companies that neglect innovation run out of things to sell. Companies that demoralize workers see performance lag. 


Although Mr Denning hopefully wrote,

We are thus about to witness a vast societal drama play out. That’s because we have reached that key theatrical moment, which Aristotle famously called 'anagnorisis' or 'recognition.'  This is the moment in a drama when ignorance shifts to knowledge.  

He then warned,

As usual with anagnorisis and the shock of recognition at a disturbing, previously-hidden truth, there is a disquieting sense that the accepted coordinates of knowledge have somehow gone awry and the universe has come out of whack. This can lead to denial and a delay in action, even though the facts are staring us in the face.

If the recognition of our error comes too late, as in Shakespeare’s Lear, the result will be terrible tragedy. If the recognition comes soon enough, the drama can still have a happy ending. We are about to find out in our case which it is to be.
Let us hope that anagnorisis is really beginning, the anechoic effect is fading, and the drama may yet have a happy ending. 

Tuesday, September 16, 2014

You Say You Want Some Revolutions? - Famed Academic Physician Dr Milton Packer's Endless Alternating Turns as Drug Company Spokesperson and FDA Advisor

Last week, we noted  we again discussed the web of conflicts of interest that is draped over medicine and health care, and seems responsible for much of our current health care dysfunction.  We have discussed examples of conflicts of interest affecting clinical research, clinical teaching, clinical care, and health care policy.  Each time I think we must have cataloged all the useful examples, a striking new one appears.

Only a few days later, yet another new variant has in fact appeared.

A New Kind of Revolving Door

A new version of the "revolving door" apparently was first noted by Public Citizen, and then reported by Ed Silverman at Pharmalot. 

The usual version of the revolving door occurs when a person transitions from a full-time job in industry to a government position which has regulatory authority or other influence over that same industry, or vica versa.  We have discussed various health care manifestations of that revolving door here.

The new version, as described by Mr Silverman, in its manifestation at the US Food and Drug Administration (FDA) is:

the agency allows some experts who serve on its advisory panels to also make presentations at other meetings of these same panels on behalf of drug makers. By allowing some people to wear different hats within a short amount of time, the advocacy group charges the FDA creates the potential for bias to creep into the proceedings.

The Public Citizen letter to the FDA summarized the problem,

In particular, a sponsor’s use of an individual who serves, or has recently served, as a voting member of an FDA advisory committee to present its case before that member’s colleagues on the committee takes advantage of the special collegiality existing among members in order to improve a company’s chances of a favorable vote. Furthermore, such a revolving door raises concerns about the objectivity of committee members who accept such paid arrangements, with FDA’s approval, at future hearings involving the same or a rival company.

Someone Familiar Going Round and Round

The Public Citizen letter used as an example one well-known academic physician who seemed to have made many revolutions in this sort of revolving door.  As summarized in the PharmaLot post,

As an example, Public Citizen cites a meeting this past March 27 of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, which was held to review an application for a Novartis drug called serelaxin to treat acute heart failure. And Milton Packer, who chairs the department of clinical sciences at UT Southwestern, appeared as a paid speaker on behalf of Novartis.

In his opening remarks, Packer disclosed that Novartis paid for his time and travel, according to the advocacy group. But because he is also considered to be a ‘special government employee,’ which is how advisory panel members are classified, he obtained permission from the FDA to participate as a paid speaker for Novartis (see page 31 here).

However, Packer served as a temporary voting member of the same FDA advisory committee less than two months earlier. Moreover, Public Citizen says this was the sixth time, since Packer first presided as chair of this committee in 1997, that he had 'spoken on behalf of and/or served as a (presumably) paid consultant' to drug makers whose meds were being reviewed at those meetings.

The other occasions in which Packer appeared before the Cardiovascular and Renal Drugs Advisory committee involved speaking on behalf of Bristol-Myers Squibb in 2002; acting as a consultant and speaker for GlaxoSmithKline in 2003; appearing as a speaker for NitroMed in 2005; appearing as a speaker for Sanofi in 2009 and acting as a consultant on behalf of Pfizer in 2010.

In fact, the Public Citizen letter also asserted that

Dr. Packer’s presence as an FDA advisory committee member at hearings extends beyond the CRDAC, as he has also participated in at least three meetings of the Arthritis Advisory Committee and served at least once on the Endocrinologic and Metabolic Drugs Advisory Committee since 2005.

We note with concern that, as with his revolving-door tenure at CRDAC, Dr. Packer has similarly worked with industry in the following capacities at non-CRDAC advisory committees while intermittently serving as a recurring member of some of these same committees:

- As a consultant to Centocor for its presentation on infliximab (Remicade) to the March 4, 2003, meeting of the Arthritis Advisory Committee;
- As an 'external expert' cited by GlaxoSmithKline at the July 30, 2007, joint meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees to discuss the cardiac ischemic risks of the thiazolidinedione diabetes drugs, with a focus on rosiglitazone (Avandia); and
- As a consultant to Boehringer Ingelheim for its presentation concerning the drug tiotropium (Spiriva HandiHaler), made before the November 19, 2009, meeting of the Pulmonary-Allergy Drugs Advisory Committee.

Summary

Dr Milton Packer served as a presumably paid spokesperson for six different pharmaceutical companies advocating for six different drugs at meetings of the FDA Cardiovascular and Renal Drugs Advisory Committee.  Over roughly the same time period he served as the chair, acting chair, or voting member of that same committee in numerous instances.  Also, Dr Packer served as a presumably paid spokesperson for one of the same drug companies, and for two additional drug companies advocating for another three drugs at meetings of three other FDA advisory committees.  On various occasions he had also served as a member of these three committees.  Parenthetically, one of the drugs for which Dr Packer, a cardiologist, advocated, Avandia, to a non-cardiologic committee was subsequently pulled from the market because of concerns about excess cardiologic complications (look here). 

Dr Packer repeatedly went back and forth between roles as a paid advocate for drug companies and as a member or chair of federal advisory committees which could influence FDA decisions about the drugs for which he advocated and which were made by the companies that employed him.


It certainly seems that Public Citizen was right in that the sorts of transitions Dr Packer made constituted multiple conflicts of interest, and that his work for multiple drug companies was likely to have distorted the recommendations of the committees on which he served.  Rapid transitions between temporary committee memberships and paid advocacy positions before such committees does seem to be a new version of the revolving door, and newly discovered type of conflict of interest.  It seems that conflicts of interest now pervade every aspect of health care, with huge cumulative effects on clinical and health policy decision making.

Note also that the person whose conflicts of interest were used as examples by Public Citizen just appeared in Health Care Renewal in another capacity.  Earlier this month we discussed a study (PARADIGM - HF) of a new drug for congestive heart failure (sacubitril) which received prominent media attention.  After various people, not limited to yours truly, pointed out that this study seemed to have multiple flaws which undercut claims that the new drug would be a "game changer," the principal investigator of the study delivered a written whupping to a critic whose writing appeared prominently on a cardiology web-site .  The scathing comeback, however, seemed based on a volley of logical fallacies, including repetitive ad hominem attacks on the critic (look here).  The PARADIGM - HF Principal Investigator was none other than the same Dr Milton Packer whose revolving door cycles were discussed above.  Note that the company that sponsored, and largely ran and designed PARADIGM - HF, and which paid Dr Packer to serve as Principal Investigator, was the same Novartis for whom Dr Packer was a spokesperson in the first example above. 

We wondered whether Dr Packer's conflicts of interest contributed to confused, illogical thinking and his apparently logically fallacious response to his critic.  Now it appears that Dr Packer has been immersed much more deeply in conflicts of interest than were apparent a few days ago.  So should he be regarded mainly as a heart failure "expert," or mainly as a paid marketer and public relations man for drug companies?  Obviously, he is both, but the mixture is not so clear.  The concern is all the more important because Dr Packer has become such a prominent medical academic.

So once again, again, again,...  we call for all conflicts to be disclosed in the interests of honesty.  Beyond that, as we have been saying for years, patients' and the public's health would benefit from an aggressive effort to reduce conflicts of interest affecting clinical and health policy decision making.    


Thursday, September 11, 2014

Higher Authorities? - Pharmaceutical Companies, Addiction Experts, and Marijuana Policy

We have often discussed the web of conflicts of interest that is draped over medicine and health care, and seems responsible for much of our current health care dysfunction.  We have discussed examples of conflicts of interest affecting clinical research, clinical teaching, clinical care, and health care policy.  Each time I think we must have cataloged all the useful examples, a striking new one appears.

So, let us get down into the weeds, so to speak, in the trendy new area of marijuana policy.

I am not about to express an opinion on whether marijuana will prove to be useful in health care, but certainly some people are advocating that it might be while others are advocating for the decriminalization or legalization of marijuana for social and health reasons.  Others, of course, do not agree.

Now Vice News, which advertises itself as "an international news organization created by and for a connected generation," has published an article by investigative journalist Lee Fang about conflicts of interest, key opinion leaders, and marijuana policy.  Its main premise was,

As Americans continue to embrace pot—as medicine and for recreational use—opponents are turning to a set of academic researchers to claim that policymakers should avoid relaxing restrictions around marijuana. It's too dangerous, risky, and untested, they say. Just as drug company-funded research has become incredibly controversial in recent years, forcing major medical schools and journals to institute strict disclosure requirements, could there be a conflict of interest issue in the pot debate?

VICE has found that many of the researchers who have advocated against legalizing pot have also been on the payroll of leading pharmaceutical firms with products that could be easily replaced by using marijuana. When these individuals have been quoted in the media, their drug-industry ties have not been revealed.

The article profiled three prominent physicians who advocate against easing rules on marijuana.  The first was Dr Herbert Kleber, a Professor of Psychiatry and Director of the Division of Substance Abuse at Columbia.  Per the article, he

has been quoted in the press and in academic publications warning against the use of marijuana, which he stresses may cause wide-ranging addiction and public health issues.

However,

what's left unsaid is that Kleber has served as a paid consultant to leading prescription drug companies, including Purdue Pharma (the maker of OxyContin), Reckitt Benckiser (the producer of a painkiller called Nurofen), and Alkermes (the producer of a powerful new opioid called Zohydro).

Then there was Dr A Eden Evins, Associate Professor of Psychiatry at Harvard and Director of the Center for Addiction Medicine at the Massachusetts General Hospital,  who

is a frequent critic of efforts to legalize marijuana. She is on the board of an anti-marijuana advocacy group, Project SAM, and has been quoted by leading media outlets criticizing the wave of new pot-related reforms. 'When people can go to a 'clinic' or 'cafe' and buy pot, that creates the perception that it's safe,' she told the Times last year.

But,

when Evins participated in a commentary on marijuana legalization for the Journal of Clinical Psychiatry, the publication found that her financial relationships required a disclosure statement, which noted that as of November 2012, she was a 'consultant for Pfizer and DLA Piper and has received grant/research support from Envivo, GlaxoSmithKline, and Pfizer.' Pfizer has moved aggressively into the $7.3 billion painkiller market. In 2011, the company acquired King Pharmaceuticals (the makers of several opioid products) and is currently working to introduce Remoxy, an OxyContin competitor.

Finally, there was Dr Mark L Kraus, described as a private practitioner and board member of the American Society of Addiction Medicine (ASAM).  He

submitted testimony in 2012 in opposition to a medical marijuana law in Connecticut. 

However,

 According to financial disclosures, Kraus served on the scientific advisory panel for painkiller companies such as Pfizer and Reckitt Benckiser in the year prior to his activism against the medical pot bill.

Mr Fang's argument that the relationships among these physicians who advocate against liberalized marijuana laws and pharmaceutical companies constitute conflicts of interest did not seem unreasonable

Studies have found that pot can be used for pain relief as a substitute for major prescription painkillers. The opioid painkiller industry is a multibillion business that has faced rising criticism from experts because painkillers now cause about 16,000 deaths a year, more than heroin and cocaine combined. Researchers view marijuana as a safe alternative to opioid products like OxyContin, and there are no known overdose deaths from pot.

Assuming the validity of this argument, the article also noted institutional conflicts of interest affecting organizations that publicly advocate against loosening marijuana restrictions,

I reported for the Nation that many of the largest anti-pot advocacy groups, including the Community Anti-Drug Coalitions for America, which has organized opposition to reform through its network of activists and through handing out advocacy material (sample op-eds against medical pot along with Reefer Madness-style videos, for example), has relied on significant funding from painkiller companies, including Purdue Pharma and Alkermes. Pharmaceutical-funded anti-drug groups like the Partnership for Drug-Free Kids and CADCA use their budget to obsess over weed while paying lip-service to the much bigger drug problem in America of over-prescribed opioids.

Summary

As we have discussed previously, narcotics addiction is a very difficult clinical and societal problem.  That makes it all the more distressing that research and teaching about, clinical practice affecting and health policy related to narcotics and narcotics addiction has been tangled up with the increasingly aggressive marketing of prescription narcotics.  Now it turns out that the companies that make and market narcotics seem to be tangled up with addiction medicine experts who are not such big fans of medical or recreational marijuana. (And it turns out once again that the physicians who claim expertise on treatment of addiction have financial relationships with the companies that market addictive medications.)

There seems to be no corner of medicine and health care untouched by the web of conflicts of interest.  So once again we call for all conflicts to be disclosed in the interests of honesty.  Beyond that, as we have been saying for years, patients' and the public's health would benefit from an aggressive effort to reduce conflicts of interest affecting clinical and health policy decision making.     

Put that in your pipe and smoke it. 

Monday, September 08, 2014

Does organized medicine need to "man up" on healthcare information technology risk and harms?

After reading a number of articles on healthcare IT problems over the past few years authored by leaders of organized medicine, please excuse me if I wonder out loud if organized medicine's leadership does not suffer from healthcare IT ignorance, low "T", or both.

Case in point, a article by Robert B. Doherty, Senior Vice President of Governmental Affairs & Public Policy, American College of Physicians that appeared in the Philadelphia newspapers blog site "The Field Clinic" today, Monday, September 8, 2014.

The article is entitled "Why doctors hate electronic health records" (no kindness in that title!) and is at http://www.philly.com/philly/blogs/fieldclinic/Why-doctors-hate-electronic-health-records.html.

After an amusing and appropriate analogy to the autobile repair industry, the article makes some good points.

First, it attacks the canard about physicians being technophobes:

... It might be tempting to dismiss the doctors complaining about EHRs as technophobes who are unwilling to embrace new technologies, but the Rand investigators say that this isn’t the case: "... our study does not suggest that physicians are Luddites, technophobes, or dinosaurs.  Physicians recognized the important advances that EHRs have enabled, particularly in accessing information remotely (like checking a patient’s test results from home) and improving compliance with guideline-based care.”

The article, unfortunately, does not go far enough to point out that the real tension is between pragmatic clinicians and information technology hyper-enthusiasts and those who stand to profit from EHR diffusion, who ignore the downsides. (For more on that issue, see my March 11, 2012 essay "Doctors and EHRs: Reframing the 'Modernists v. Luddites' Canard to The Accurate 'Ardent Technophiles vs. Pragmatists' Reality" at http://hcrenewal.blogspot.com/2012/03/doctors-and-ehrs-reframing-modernists-v.html.)

The article's author offers relatively standard and obvious "prescriptions":

... The solution isn’t going back to paper records, but designing EHRs that work for doctors and patients. Here are some obvious steps:
  • EHRs should provide physicians with abstracted, relevant clinical data in the most user-friendly way possible, rather than dumping reams of data on them that make it hard to extract the useful from the extraneous.
  • EHRs should supplement but not substitute for physician decision-making, providing doctors with evidence on the effectiveness of different drugs and tests in the least intrusive and least repetitive manner possible.
  • EHRs should facilitate face-to-face interactions between doctors and their patients not detract from them.  (In my most recent visit to my own primary care doctor. he spent almost the entire time looking at his EHR, rather than making eye contact with me). 
  • EHRs should make it as easy and quick as possible for physicians to document in the record the care provided to the patient.
  • EHRs must become fully interoperable, able to seamlessly exchange secure patient data with other EHRs.
The government has a lot of EHR standards, but the only one that really should matter is how useful EHRs are are in helping physicians take better care of patients.

That said, the failure to address the significant downsides, including compromised safety from bad health IT and actual harms, among others, is disappointing.  I have rarely if ever seen officials in organized medicine address that issue head-on.

Ironically, the author points out that RAND investigators wrote:

... The overarching problem, the authors contend, is that “no other industry, to our knowledge, has been under a universal mandate to adopt a new technology before its effects are fully understood...

Those "effects" happen to include not just clinician inconvenience, but direct patient harm, a phenomenon that in 2014 is poorly understood as admitted by FDA, the Institute of Medicine and numerous others.  That unacceptable state of affairs largely due to systematic impediments to understanding the magnitude of harms - that is, willful and deliberate blindness by those who know better (see the blog link below for more on these assertions if you are not a regular reader here).

My letter to Mr. Doherty at ACP speaks for itself:
From: Silverstein,Scot
Sent: Monday, September 08, 2014 2:43 PM
To: Robert Doherty, American College of Physicians
Subject: RE: "Why doctors hate electronic health records"
Dear Mr. Doherty,

Read with interest your piece "Why doctors hate electronic health records" at http://www.philly.com/philly/blogs/fieldclinic/Why-doctors-hate-electronic-health-records.html

Are you aware another reason for doctors, especially hospital-based ones, to "hate" EHRs (or, more correctly, the hyper-enthusiasts who push them and the industry that creates them) is due to the potential of these unregulated and poorly-engineered systems to contribute to or be causative of patient harms?

I have been expert witness on the Plaintiff's side in numerous cases where this has occurred...after my own mother was tragically and fatally injured in just such an accident.

These were cases where paper would have been more resilient.

FYI, in case you were unaware:

ECRI institute's voluntary 2012 "Deep Dive study of EHR" finding of 171 IT-related "incidents" in 36 member PSO hospitals in 9 weeks, resulting in 8 injuries and 3 possible deaths, is an example of why physicians ought "hate" the state of the health IT industry and its true lack of regulation, pre- and post-market surveillance, and other such factors prevalent in other mission-critical sectors.

More on these issues is at my blog post at the blog site of the Foundation for Integrity and Responsibility in Medicine, a 501(c)(3), at http://hcrenewal.blogspot.com/2014/04/fda-on-health-it-risk-reckless-or.html

I am educating the Plaintiff's Bar on these issues at AAJ national and state chapter meetings.

I have zero tolerance for bad health IT, and complacent clinical users of bad health IT.

Sincerely,

Scot Silverstein, MD

In fact, it should be ACP, AMA, the state societies etc. performing the education on the issue of health IT harms, not just me and a small group of patient's-rights-minded "health IT iconoclasts."

One day, I hope organized medicine will start taking "T" supplements and do what needs to be done to compel this industry - and the government that should be regulating it effectively - to man up. 

-- SS

Friday, September 05, 2014

Logical Fallacies in Defense of the PARADIGM - HF Trial of Valsartan - Sacubitril, Suppsedly the "Game Changer" for Heart Failure

We frequently discuss how commercial sponsors manipulate clinical research to serve their interests.  There have been many cases of commercially sponsored controlled trials ostensibly designed to assess their sponsors' products manipulated to make these products look better.

Unfortunately, often such manipulation seems to escape public notice.  What skepticism they may generate often gets little notice, an example of the anechoic effect.  Very rarely do the people responsible for the trial deign to address skeptical criticism. 

However, we recently noted that cogent criticism of a very recently published trial got some circulation, leading to a dialogue with the trial's principal investigator.  The results seemed to show why those involved with manipulated sponsored trials often try to just ignore criticism.

Introduction - the PARADIGM - HF Trial of Valsartan - Sacubitril


As we recently posted, based on a new article now online in the New England Journal of Medicine, a combination of a new drug, sacubitril, in a new class, naprilysin inhibitors, with an older drug, valsartan, an angiotensin receptor blocker (ARB), has been hailed as a "game changer" for patients with heart failure.  However, although the study (entitled PARADIGM - HF) had many good features, it also had some major problems which made its interpretation difficult, and made the hype about "new hope" seem excessive.  Unbeknownst to me when I wrote the post, some pithy overlapping criticisms of PARADIGM - HF by Dr Vinay Prasad were posted on CardioExchange.

Surprisingly, Dr Prasad's post elicited a lengthy comment by Dr Milton Packer, the principal investigator of PARADIGM - HF, defending the study's methods.  This resulted in a back-and-forth between him and Dr Prasad.  (Available by subscription only.)  This seems to be on of those rare instances in which a pillar of the medical establishment was willing to defend the way things are done these days in health care, and in this case, the way commercially sponsored randomized controlled trials are designed.

In my humble opinion, this exchange illustrated one reason that most criticisms about flaws in commercially funded clinical research get the silent treatment: there really are not good explanations for them, other than they resulted from the intention to increase the likelihood that the sponsors' products would look better than they really are.

Let us consider in detail some of the written comments by Dr Packer addressing two major criticisms by Dr Prasad.

The Question about the Choice of Comparator

Dr Prasad and I both questioned the choice of the drug to which valsartan - sacubitril was compared.  Dr Prasad wrote,

In PARADIGM-HF, oral enalapril was dosed up to 10 mg twice daily, whereas LCZ696 was dosed up to 200 mg twice daily (which includes a cumulative 320 mg of valsartan). The problem is that 320 mg is the maximum HF dose of valsartan per drug labeling, but enalapril can be dosed up to 40 mg daily (20 mg twice daily) — double the maximum dose proscribed per protocol.

So,

In effect, drug dosing in PARADIGM-HF was a 'straw man' comparison. The reported outcomes may be entirely a consequence of more ARB versus less ACE inhibitor. That is reason enough to doubt the findings. Sacubutil, the novel drug, could have been a sugar pill, and the results may well have turned out the same. But there are two more good reasons to be skeptical.

Note that in effect Dr Prasad charged that the entire trial was based on a logical fallacy, the "straw man" fallacy.

Dr Packer's Response: Red Herrings, Ad Hominem Fallacies, and Appeals to Authority

Red Herring - Comparison to Trial with a Different Patient Population

Dr Packer made several responses to this criticism.  First,  he asserted that using the maximum dose of enalapril as a target dose would have been inappropriate,

Dr. Prasad proposes that the dose of enalapril was too low, and we should have used 40 mg daily of enalapril as a comparator. However, when 40 mg of enalapril daily has been used in a clinical trial (CONSENSUS), these extremely high doses were poorly tolerated due to hypotension and renal insufficiency.

However, that appears to be to be an example of the red herring fallacy.  The PARADIGM - HF trial was meant to include patients with mild to severe symptoms of CHF (CHF classes II - IV), although it actually included a few (about 5%) patients with no symptoms (class I).  However, as Dr Prasad pointed out in his later comeback,

Dr. Packer suggests that CONSENSUS trial proves that enalapril 40 cannot be given safely. It is worth noting this trial enrolled only NY Heart Classification IV patients, while these were less than 1% of pts in PARADIGM HF. Many patients in PARADIGM HF might well have been able to tolerate and benefit from enalapril 40mg.

So Dr Packer's argument based on a trial of only the sickest patients with CHF seems likely not be relevant to discussion of a trial of patients with much milder disease.

Red Herring - Physiologic Changes vs Patient-Centered Outcomes

Then, Dr countered Dr Prasad's concern that the design of PARADIGM - HF could not distinguish whether the apparent benefits of valsartan (at maximum dose) and sacubitril versus enalapril (at a moderate dose) were due to the valsartan alone versus the combination thus,

Furthermore, Dr. Prasad can provide no evidence whatsoever than valsaratan 160 mg BID produces more blockade of the renin-angiotensin system than enalapril 10 mg BID. It is simply not true.

This seems to be an even better example of the red herring fallacy.  The argument is not about the physiological changes the drugs may or may not produce.  It is about the design of a clinical trial and how that design could affect interpretation of patient-centered outcomes.  Degree of renin-angiotensin system blockade may not directly predict survival, hospitalization, functional status, etc.

Red Herring - References to a Trial of Valsartan in Addition to ACE Inhibitors

Appended to the above, Dr Packer wrote,


In fact, valsartan 160 mg BID does not even have a mortality effect when compared with placebo, whereas enalapril 10 mg BID does have a survival benefit.

It later became apparent that the evidence he felt supported this assertion came from yet another trial with an alphabet soup name, Val - HEFT.  But, as Dr Prasad argued, this was yet another red herring,

The VAL-HEFT trial– where Valsartan 160 BID was no better than placebo– occurred in the setting where 92% of patients were already on an ace-inhibitor. As such, it cannot be used to say what the effect of valsartan is among patients not taking an ace-inhibitor, as was the case in PARADIGM-HF.

To explain a bit, the Val - HEFT trial enrolled patients who were nearly all already taking an ACEI, including enalapril.  So its data could only speak to the question of whether adding valsartan to an ACEI has an effect, not whether valsartan alone is efficacious in CHF.  It does not appear that there has ever been a large, long-term randomized controlled trial that tested valsartan versus placebo for CHF.   So Dr Packer seemed to have supplied another quite large red herring.

Of course that raises the question of why  PARADIGM - HF only assessed the combination of  sacubitril plus valsartan, rather than sacubitril combined with other ARBs.  This question was not directly addressed in the exchange between Dr Packer and Dr Prasad.  Parenthetically, note that valsartan is sold by Novartis, the sponsor of PADADIGM - HF, as Diovan.

Dr Packer only complicated things later by writing,


if Dr. Prasad dismisses the evidence from Val-HeFT, he eliminates ALL of the evidence that supports the use of valsartan in heart failure. If he sets the Val-HeFT trial aside, what evidence is there that valsartan 160 mg BID does ANYTHING in heart failure?

Again, Dr Packer was the one supposedly responsible for the choice of valsartan as the ARB to combine with sacubitril.

In summary thus far, I could not find any instance in the exchange in which Dr Packer logically used evidence to explain why his trial compared valsartan (targeted to maximum dose) plus sacubitril to enalapril (targeted to a moderate dose).  Instead, his arguments seemed to consist of multiple examples of the red herring fallacy.

Ad Hominem - Dr Prasad's Degree of Understanding of the Heart Failure Literature

Instead, he also threw in some additional general points which appeared to be rather gratuitously fallacious, To start,

 
I wish that Dr. Prasad understood the field of heart failure trials better than he does,

Then,

I wish Dr Prasad understood the heart failure literature better.


These seem to be examples of the ad hominem fallacy.  Rather than addressing the logic and evidence used by Dr Prasad, Dr Packer implied that Dr Prasad simply lacks understanding. Dr Prasad's polite response was,


Dr. Packer could tighten his posts by reducing the number of times he wishes I understood the heart failure literature better.
Appeal to Authority - Dr Packer's and Colleagues' Implied Superior Expertise on the Medical Literature

That did not prevent Dr Packer from coming back with,

 
I suggested that Dr. Prasad become more familiar with the medical literature because it would save him considerable time in formulating useful arguments.

With this repetition, Dr Packer seems to be not only using the ad hominem fallacy, but implying the fallacy of the appeal to authority. The implication is that Dr Packer clearly is an expert, and Dr Prasad is not, and the expert should be heeded. Just to underline this, Dr Packer later wrote,

Dr. Prasad suggests that others share his concerns. If he were here in Barcelona at the ESC meeting, he would know that that was not the case. However, I realize that It is common for those who seek only to win debates to claim that others agree with them. But Dr. Prasad, wishing that people agree with you does not make it true.

That just makes it worse. The implication is that all the experts in Barcelona agree with Dr Packer, and hence as a group they must be right. By the way, it is obvious from our previous blog post, comments on it, and other comments on the CardioExchange exchange that there are at least other people who agree with Dr Prasad.

Appeals to Authority - The New England Journal of Medicine and the US Food and Drug Administration Must Always be Totally Right

Not to leave it there, Dr Packer added as general comments several other appeals to authority.  At the end of his first set of comments there was this,

The real lesson of PARADIGM-HF is that combined angiotensin receptor neprilsyin inhibition is superior to inhibition of the renin-angiotensin system alone in patients with chronic heart failure. That is the conclusion of our paper, which passes stringent peer review in the New England Journal of Medicine.

The implication is that no paper published in the New England Journal of Medicine should ever be questioned about anything.  Also,


 
it does not appear that you are aware of the criteria that the FDA uses to evaluate or approve new drugs for cardiovascular disease.

This added the appeal to authority that since the FDA approved this trial, there must be nothing major wrong with it, to another implied ad hominem about Dr Prasad's lack of awareness.

Thus it seemed that Dr Packer's defense of his PARADIGM - HF study's choice of drugs to compare was based almost entirely on a string of logical fallacies, rather than logic and evidence.

The Question of Run-In Period Bias

Dr Prasad's other major criticism of his trial had to do with its use of active run-in periods.  He wrote,

The reason why drug run-in periods are problematic is discussed at length in the literature. In short, run-in periods exclude intolerant and nonadherent patients, foster spuriously large treatment effects, and (most troubling) create inclusion criteria that are irreproducible — i.e., that apply to no population we can clearly describe, as reasons for dropout are multifaceted and unique.

Even more concerning is that drug run-in periods test a different question than the one we think we are testing. In PARADIGM-HF, the run-in tested whether sticking with LCZ696 or switching to enalapril is better for HF patients who have taken and tolerated enalapril followed by LCZ696. It effectively turns the trial into a withdrawal study. If stopping LCZ696 is harmful, that counts against enalapril.

Dr Packer's Response: Appeals to Common Practice 

Dr Packer's main argument in defense of the run-in period involved yet another logical fallacy, the appeal to common practice, for example,
  
Dr. Prasad seem ill-informed here. Drug run-in periods are not a controversial study-design choice. In fact, this type of design is strongly preferred because it closely mimics clinical practice.

Again,

I wish I understood Dr. Prasad’s arguments against run-in periods. We have used them in many heart failure trials, and it was used in the SOLVD Treatment Trial,...

Dr Prasad ultimately responded so as to underline the essence of the fallacy,

The fact that many (and often industry sponsored) studies use drug run in periods is not a justification for their use. 

Summary

The recently published paper reporting the results of PARADIGM - HF has already generated considerable media hype (and an uncritical editorial) proclaiming valsartan - sacubitril as a new wonder drug for congestive heart failure.  While the trial was not without good features, several critics, including Dr Vinay Prasad and yours truly, suggested the study had multiple problems which make its results difficult to interpret.  The Principal Investigator of the study, Dr Milton Packer, chose to publicly defend his trial, yet so far his defense seems built more on logical fallacies than on logic and evidence.  After he published his remarks in defense of the trial, the hype seems no more justified than it did before.

Not only was PARADIGM - HF sponsored by Novartis, but many of its investigators had ties to Novartis and other pharmaceutical companies.  Dr Packer should be applauded for disclosing clearly the number of companies with whom he works in his dialogue with Dr Prasad.

Competing interests: Personal fees from AMAG, Amgen, BioControl, CardioKinetix, CardioMEMS, Cardiorentis, Daiichi, Janssen, Novartis, and Sanofi.

However, not only is it likely that financial relationships with commercial health care firms influence health care professionals to be more favorably disposed to these firms' products, but also such conflicts of interest may cause conflicted, and hence confused thinking.  As  I have noted before, Dr Joe Collier said, "people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult."  [Collier J. The price of independence. Br Med J 2006; 332: 1447-9. Link here.]  

This all adds to the argument that society needs to reconsider its delegation of the responsibility for much clinical research to the companies that make the drugs, devices, and other goods and services used in health care.  The temptation for them to manipulate the results to improve their marketing is too great.  The temptation for the health care professionals involved to go along to get along with the rich sponsors is too great.  It may be less profitable for some individuals, but it would be much better for patients' and the public's health if research involving people, particularly experiments (clinical trials) involving patients, were directly funded by, and designed, implemented, and analyzed by people without vested interests in the results turning out in favor of particular commercially produced goods or services. 

EHR safety, a false sense of security, and epistemological problems in the Medical Informatics community

Neil Versel is an author of many articles about healthcare information technology.  He recently published "Patient safety in the balance: Questions mount about EHRs and a wide range of patient safety concerns" (http://www.healthcareitnews.com/news/patient-safety-balance) in Healthcare IT News,

a sidebar on my views "A 'false sense of security'" (http://www.healthcareitnews.com/news/false-sense-security).

I thought my feedback back to him would be of interest, centering on a published comment of the typical hyper-enthusiast variety made by a prominent member of my Medical Informatics professional community.  The view exemplifies a widely-held but erroneous (and decidedly non-scientific) viewpoint in my professional community - and many others, including government -  regarding drawing conclusions in the face of significant evidentiary gaps and impediments regarding harms.

Here are my emails to Mr. Versel.  They speak for themselves, especially the short second supplementary email seen at the bottom of this blog post

-- SS

-------------------------------------------------------------


EMAIL #1:

From: Silverstein,Scot
Sent: Friday, September 05, 2014 10:05 AM
To: Neil Versel
Subject: Re:" A 'false sense of security'"

Neil,

Thanks for citing me in your article at http://www.healthcareitnews.com/news/patient-safety-balance, http://www.healthcareitnews.com/news/false-sense-security etc.

Want to call your attention to one of my largest disappointments and frustrations in health IT that evolved over the past decade or two, namely, cheerleading for the technology in the face of commonly understood Western science and epistemology ("the theory of knowledge, especially with regard to its methods, validity, and scope. Epistemology is the investigation of what distinguishes justified belief from opinion").

My concerns are best exemplified by the comment posted at the article site by a prominent member of my Medical Informatics professional community:


"The question is not whether EHRs are safe or not; sometimes they are, and sometimes they are not. The real question is whether they are safer than paper records, and the weight of scientific evidence is that they are."

The actual truth, considering the explicit statements with explicit reasons given by IOM, FDA, ECRI, and others as to why what we know about electronic harms is incomplete ("tip of the iceberg", see below), is that "while the potential for electronic systems to be safer than paper exists, the scientific evidence is inadequate to make any statement about comparative safety on the ground."

The data inadequacy is made far worse by the known and stated systematic impediments to discovery and diffusion of the harms, and a lack of robust studies on ACTUAL harms due to paper-based record keeping, especially and critically regarding optimal and well-staffed paper systems.  (Try a Medline search on that topic!)

The hyper-enthusiasts who favor the theoretical over reality on the ground and who push for speedy national rollout without proper safeguards, surveillance and regulation, are, in fact, killing people. [I.e, whose injuries and deaths at the hands of bad health IT were otherwise preventable had appropriate industry safeguards been in place - ed.]

There is actually nothing to argue, nothing to debate on this issue.

Some material backing up these assertions is below, mostly already covered in my blog-based 11 points.  [As at http://hcrenewal.blogspot.com/2014/04/fda-on-health-it-risk-reckless-or.html - ed.]

Cheers,

Scot

------------------------------



Examples: 

1)  IOM report on HIT safety, 2012 (as I report at http://hcrenewal.blogspot.com/2012/03/doctors-and-ehrs-reframing-modernists-v.html , midway down):


.. While some studies suggest improvements in patient safety can be made, others have found no effect. Instances of health IT–associated harm have been reported. However, little published evidence could be found quantifying the magnitude of the risk.
Several reasons health IT–related safety data are lacking include the absence of measures and a central repository (or linkages among decentralized repositories) to collect, analyze, and act on information related to safety of this technology. Another impediment to gathering safety data is contractual barriers (e.g., nondisclosure, confidentiality clauses) that can prevent users from sharing information about health IT–related adverse events. These barriers limit users’ abilities to share knowledge of risk-prone user interfaces, for instance through screenshots and descriptions of potentially unsafe processes. In addition, some vendors include language in their sales contracts and escape responsibility for errors or defects in their software (i.e., “hold harmless clauses”). The committee believes these types of contractual restrictions limit transparency, which significantly contributes to the gaps in knowledge of health IT–related patient safety risks. These barriers to generating evidence pose unacceptable risks to safety.[IOM (Institute of Medicine). 2012. Health IT and Patient Safety: Building Safer Systems for Better Care (PDF). Washington, DC: The National Academies Press, pg. S-2.]

Also in the IOM report:


… “For example, the number of patients who receive the correct medication in hospitals increases when these hospitals implement well-planned, robust computerized prescribing mechanisms and use barcoding systems. But even in these instances, the ability to generalize the results across the health care system may be limited. For other products— including electronic health records, which are being employed with more and more frequency— some studies find improvements in patient safety, while other studies find no effect.
More worrisome, some case reports suggest that poorly designed health IT can create new hazards in the already complex delivery of care. Although the magnitude of the risk associated with health IT is not known, some examples illustrate the concerns. Dosing errors, failure to detect life-threatening illnesses, and delaying treatment due to poor human–computer interactions or loss of data have led to serious injury and death.”

2)  FDA Internal memo on HIT risk, 2010 (as i report at http://hcrenewal.blogspot.com/2010/08/smoking-gun-internal-fda-memorandum-of.html):


... In summary, the results of this data review suggest significant clinical implications and public safety issues surrounding Health Information Technology. The most commonly reported H-IT safety issues included wrong patient/wrong data, medication administration issues, clinical data loss/miscalculation, and unforeseen software design issues; all of which have varying impact on the patient’s clinical care and outcome, which included 6 death and 43 injuries. The absence of mandatory reporting enforcement of H-IT safety issues limits the number of relevant MDRs and impedes a more comprehensive understanding of the actual problems and implications.


  This is especially true considering the FDA's own noted limitations of their information sources:




Limitations of the MAUDE search and final subset of MDRs include the following:

1. Not all H-IT safety issue MDRs can be captured due to limitations of reporting practices including
... (a) Vast number of H-IT systems that interface with multiple medical devices currently assigned to multiple procodes making it difficult to identify specific procodes for H-IT safety issues;
... (b) Procode assignments are also affected by the ability of the reporter/contractor to correctly identify the event as a H-IT safety issue;
... (c) Correct identification by the reporter of the suspect device brand name is challenged by difficulties discerning the actual H-IT system versus the device it supports.
2. Due to incomplete information in the MDRs, it is difficult to unduplicate similar reports, potentially resulting in a higher number of reports than actual events.
3. Reported death and injury events may only be associated with the reported device but not necessarily attributed to the device.
Memo: H-IT Safety Issues
4 Correct identification by the reporter of the manufacturer name is convoluted by the inability to discern the manufacturer of the actual H-IT system versus the device it supports.
5 The volume of MDR reporting to MAUDE may be impacted by a lack of understanding the reportability of H-IT safety issues and enforcement of such reporting.


3)  Jeff Shuren MD JD, head of FDA CDRH (as I report at http://hcrenewal.blogspot.com/2010/02/fda-on-health-it-adverse-consequences.html):


The Office of the National Coordinator for Health IT held a meeting of the HIT Policy Committee, Adoption/Certification Workgroup on February 25, 2010. The topic was "HIT safety." The agenda, presenters and presentations are available at this link.

At this meeting FDA testimony was given by Jeffrey Shuren, Director of FDA’s Center for Devices and Radiological Health. Dr. Shuren noted several categories of health IT-induced adverse consequences known by FDA. This information was striking:

He wrote:


... In the past two years, we have received 260 reports of HIT-related malfunctions with the potential for patient harm – including 44 reported injuries and 6 reported deaths. Because these reports are purely voluntary, they may represent only the tip of the iceberg in terms of the HIT-related problems that exist.

Even within this limited sample, several serious safety concerns have come to light. The reported adverse events have largely fallen into four major categories: (1) errors of commission, such as accessing the wrong patient’s record or overwriting one patient’s information with another’s; (2) errors of omission or transmission, such as the loss or corruption of vital patient data; (3) errors in data analysis, including medication dosing errors of several orders of magnitude; and (4) incompatibility between multi-vendor software applications and systems, which can lead to any of the above.

4)  ECRI Institute Deep Dive study of health IT safety (as I report at http://hcrenewal.blogspot.com/2013/02/peering-underneath-icebergs-water-level.html):

Participating facilities submitted health IT related events during the nine-week period starting April 16, 2012, and ending June 19, 2012. ECRI Institute PSO pulled additional health IT events that were submitted by facilities during the same nine-week period as part of their routine process of submitting event reports to ECRI Institute PSO’s reporting program. The PSO Deep Dive analysis consisted of 171 health IT-related events submitted by 36 healthcare facilities, primarily hospitals

(There were 8 injuries and 3 possible deaths associated with these 171 IT-related events over just 9 weeks, suggesting a damn serious problem way ahead of paper errors.)

5)  Statement by Medical Director of ECRI, same link as above:

Karen Zimmer, MD, medical director of the institute, says the reports of so many types of errors and harm got the staff's attention in part because the program captured so many serious errors within just a nine-week project last spring.  The volume of errors in the voluntary reports was she says, "an awareness raiser."

"If we're seeing this much under a voluntary reporting program, we know this is just the tip of the iceberg; we know these events are very much underreported."

6)  ECRI's continuing concerns based on continuous data submitted by their PSO member hospitals that health IT systems are "one of the top ten (and in fact in 2014, risk #1) technology risks in healthcare" (as I report at http://hcrenewal.blogspot.com/2014/04/in-ecri-institutes-new-2014-top-10.html)


This is a short list, but you get the idea about making any statements about comparative risks of paper v. electronic.

-----------------------------------------------------------------------------------------
 

EMAIL #2: 

 From: Silverstein,Scot  
Sent: Friday, September 05, 2014 10:08 AM
To: Neil Versel
Subject: RE: Re:" A 'false sense of security'"

Not to mention that the "real" question is NOT "whether they [electronic systems] are safer than paper records."

The real question is:  is it ethical, based on the current clinical reality and incomplete state of knowledge, to push this technology on patients?

I also could add to that question:  "...especially without informed consent?"

Scot


-----------------------------------------------------------------------------------------

-- SS  

Wednesday, September 03, 2014

Sacubitril - Valsartan, a "New Threshold of Hope" or Hype for Heart Failure?

Summer must be over, because the next new blockbuster drug appears to be here.  At the end of August, the media heralded the results of a study of a new product for congestive heart failure (CHF) from Novartis.

Novartis' New "Game Changer"

The New York Times article was fairly restrained, simply saying it

has shown a striking efficacy in prolonging the lives of people with heart failure

The Reuters article's headline said

New Novartis drug may upend heart failure treatment

In Forbes, Matthew Herper called it a

Game Changer

The accompanying editorial in the New England Journal of Medicine (1) suggested the drug

may well represent a new threshold of hope for patients with heart failure

On the heels of the debate about the high price of Sovaldi, Gilead's drug similarly touted as a game changer for the also common disease, hepatitis C (look here), almost immediately the concerns about cost followed.  Another Reuters article quoted the past president of the European Society of Cardiology,

We are entering a new era of treatment and, of course, it will cost a lot of money, which is a problem

This blog was late to the party for Sovaldi, and did not get to examine the evidence used to support its ostensibly wondrous properties until a while after it was published, and after the drug was approved.  Therefore, I thought we should examine the new evidence about Novartis' new drug now, before the drug is reviewed for marketing approval.

Congestive Heart Failure

First, let me give a very informal review of congestive heart failure (CHF).  CHF is a syndrome that is the final common pathway for many patients with heart disease.  It can be commonly caused by prolonged hypertension, coronary artery disease (often after one or more myocardial infarctions, or heart attacks), cardiac valve disease, or various problems with the heart muscle (cardiomyopathies).  In CHF, the heart cannot pump sufficiently to meet the body's needs.  The body responds in various ways, not all advantageous.  There are two main types of heart failure.  In one, systolic dysfunction, the heart's pump function, measured by its ejection fraction, is directly reduced.  In the other, sometimes called diastolic dysfunction, the heart becomes stiff, and hence it may not fill with blood adequately.  In either case, a common response is accumulation of fluid.  Fluid can accumulate in the lungs, causing breathlessness.  CHF patients often are fatigued, breathless, find it hard to do physical activity, and may have swelling of the legs or abdomen (edema).

Starting more than 20 years ago, a series of landmark clinical trials found that various types of medication could be used to modify the often disadvantageous compensatory mechanisms evoked by CHF with systolic dysfunction.  Controlled trials showed these medications could reduce symptoms, reduce hospitalizations, and prolong life.  These medications included those that affected the renin-angiotensin system, used by the body to control blood flow and pressure, including angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs).  Also found to be efficacious were beta-blockers and mineralocorticoid blockers. At this point, all these medications are available in cheap, generic form in the US.

Review of the New Study of Sacubitril and Neprilysin Inhibtion

So let us examine the article just published online that reports a trial of Novartis' new drug.(2)

The new Novartis medication is sacubitril, which inhibits an enzyme called neprilysin, which degrades various active compounds in the body.  Inhibition of the enzyme and the resultant increase in the level of these compounds seems to favorably affect the disadvantageous compensation mechanisms found in CHF.

A previous effort to develop a neprilysin inhibitor found that it produced an unacceptable risk of a serious side-effect, angioedema, when combined with an ACE inhibitor.  So the current study involved another neprilysin inhibitor, sacubitril, combined with a angiotensin receptor blocker, valsartan, sold by Novartis under the trade name Diovan.

The trial had many good features.  It was large, including 8442 patients randomized.  It followed patients for longer than the short-term, a median of 27 months.  Most importantly, it assessed real clinical outcomes that might be important to patients (that is, "patient-centered outcomes,") including death, acute hospitalization, and a measure of health status and physical function, the Kansas City Cardiomyopathy Questionnaire (KCCQ).  

So far, so good.  However, a close read revealed some major and some minor problems.
  
Low Dose of Comparator 

This is a bit complex so bear with me.  

The study assessed a combination of sacubitril and valsartan versus a well-known ACE inhibitor, enalapril.  The target dose of the sacubitril and valsartan, rather confusingly called LCZ696, was 160 mg of valsartan twice daily, for a total of 320 mg/ day of valsartan.  The target dose of enalapril was 10 mg twice daily, for a total of 20 mg.

Note that both ACEIs like enalapril and ARBs like valsartan are considered appropriate first line treatment of CHF with systolic dysfunction.  In the most recent ACCF/ AHA guideline for heart failure, the maximum suggested dose of enalapril is 10-20 mg twice a day, and of valsartan, 160 mg twice a day.  Previous studies have suggested that pushing these doses as high as patients can tolerate improves outcomes.  

So the current study compared a targeted maximum dose of valsartan (plus sacubitril) to a less than maximum dose of enalapril.  The article did not explain why the study did not call for a maximum dose of enalapril, or indeed why valsartan plus sacubitril was not compared to valsartan alone. 

Thus the advantages of valsartan plus sacubitril found in the study could be entirely due to the superiority of maximum doses of valsartan versus moderate doses of enalapril.  I do not believe the study design can allow conclusions to be drawn about the efficacy of sacubitril.

 Note that this problem was noted in an online comment on the article by Dr Martin Nitschke.   

Choosing to compare the new drug to a less than maximally efficacious dose of the comparator medicine could make the new drug appear to be more efficacious than it actually is.  This apparent major design problem has been listed as one of the ways commercially sponsored studies may be manipulated to make the sponsors' products appear better.  The particular tactic of conducting a trial "against a treatment known to be inferior" was listed in a 2005 article on clinical research manipulation by Richard Smith.(3)


Active Run-In Period

Before patients were enrolled in the trial, they went through two "run-in" periods.  In the first, they were switched from their previous doses of ACEIs or ARBs to enalapril, up to 10 mg twice daily.  Patients unable to tolerate this were not randomized.  

Then the patients were switched from enalapril to valsartan 160 mg plus sacubitril up to .  Again, if they failed to tolerate this, they were also not randomized.  

The article noted that substantial patients were disqualified during these active run-in periods.  During the enalapril period, of 10,513 patients, 1102 were dropped from the study, including 591 (5.6%) due to an adverse effect, 66 (0.6%) due to an abnormal test results, and 49 (0.5%) who died.  During the valsartan plus sacubitril period, of 9419 patients, 977 were dropped, including 547 (5.8%) for adverse effects, 58 (0.6%) for abnormal test results, and 47 (0.5%) who died.  

There are major problems with such active run-in periods.  First, by eliminating patients who had adverse effects from the main results, they make the adverse effect rate appear smaller.  

Second, they raise questions about the patient population to whom the study results apply.  The study results only clearly apply to patients who are known to be able to tolerate valsartan and sacubitril.  In practice, should the drug be approved, at that time the only such patients would be those who already participated in trials.  (Of course, the results only apply to patients known to be able to tolerate enalapril.  This drug, however, has been on the market for years, and is widely used for problems, like hypertension, other than CHF.  So there are already quite a few patients known to tolerate it.)

The problems with interpreting studies that included active run-in periods were clearly described in an article by Pablos-Mendez et al in 1998.(4) 

Failure to Consider Adverse Effects Specific to Sacubitril

Valsartan and enalapril are now old drugs.  Their adverse effects are well known.

Sacubitril is a new drug in a new class.  It inhibits an enzyme that in turn affects the metabolism of many substances.  Thus, it is possible it has widespread effects, and may have multiple, and possibly unusual side-effects.

Yet the current study did not apparently include any efforts to anticipate and attempt to assess such side effects.  This problem was pointed out in a comment by Dr Ivan Boyadzhiev.

Failure to consider specific adverse effects may mean these effects are overlooked.  Thus, it is possible that the new drug has adverse effects that go beyond what are addressed in the article. 

Large Numbers of Sites and Quality Control

The study was done in 1043 centers in 47 countries.  The list of investigators took up six pages of the supplementary documentation.  Thus the average number of patients recruited per center was less than nine.

It seems improbable that a study involving so many investigators and centers, most of whom must have devoted little of their time and effort to this particular study, would have adequate quality control.  One indicator that quality control may have been a problem was that although the study inclusion criteria included patients with class II-IV heart failure, about 5% of study patients had class I heart failure.

The article and the supplementary material did not discuss study coordination or quality control.  It is not possible to tell whether any such problems with quality control may have distorted the study's results.

Lack of Generalizability in the Patient Population

The complete list of exclusion criteria, only appearing in the supplementary material, was extensive.  Patients with many common problems were supposed to be excluded, and the definition of the some exclusion criteria were vague and subjective.  These problems included coronary or carotid artery disease "likely to require" surgical or percutaneous intervention within 6 months, "history of severe pulmonary disease," "any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drugs," including inflammatory bowel disease, duodenal or gastric ulcers, evidence of liver disease, and "presence of any other disease with a life expectancy of less than 5  years."

CHF patients are commonly elderly and have other medical problems.  Thus the study's results may not generalize to many patients with CHF in real-life. 

 Summary

It would certainly be nice to have a new medicine to improve the management of chronic CHF.  Sacubitril may have promise to do so.  Unfortunately, the clinical trial that just generated much favorable publicity ahead of regulatory consideration of this drug had major, possibly fatal flaws.  Use of a probably non-comparable and inferior "comparator" medication made it impossible to tell whether sacubitril actually is efficacious.  Use of an active run-in period, and failure to consider whether this new drug may have unexpected side-effects made it likely that the study underestimated its adverse effects.  Study results may not generalize to many real-life patients.  There are reasons to be concerned about whether the quality of study implementation was adequate.

Therefore, all the enthusiasm about this drug may be premature, and does not appear to be evidence-based.  That clinical research sponsored by organizations that sell health care goods and services may be manipulated to make the sponsors' products look better than they really are is now an old story.  We have seen multiple instances in which drugs and devices turned out to be less efficacious and/or more dangerous than originally advertised.  Excess enthusiasm about such new innovations may drive up costs, and worse, hurt patients.  Physicians, other health care professionals, and those concerned about health policy ought to be much more skeptical about every new instance of a purportedly wondrous innovation. 

 Evidence-based medicine rigorously applied suggests that individual health care and health policy decisions should be driven by the best available evidence, mostly from clinical research, about the benefits and harms of tests, treatments, programs, and so on, in the context of what outcomes matter to patients.  The skepticism EBM should engender lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.

ADDENDUM (3 September, 2014) - See also post by Dr Vinay Prasad on the CardioExchange site.  He drew similar conclusions about the choice of comparator, and the active run-in period, and added a new concern about the early stopping of the trial.  The comments include a - ahem - vigorous exchange between Dr Prasad and Dr Milton Packer, the Principal Investigator of the trial.  IMHO, Dr Packer did not completely understand or appreciate the points made by Dr Prasad.  Also, see our later blog post on this exchange here.

ADDENDUM (9 September, 2014) - See also a post by Gary Schwitzer on the HealthNewsReview.org blog that summarizes other critical online comments about the PARADIGM - HF study.  In particular, Dr Richard Lehman on his Journal Review blog on the British Medical Journal website wrote this scathing paragraph:

 And now, alas, to the much-vaunted PARADIGM-HF trial. This has been hyped as the biggest breakthrough in heart failure for at least 20 years.  A fixed dose of enalapril was compared with a substance called LCZ696. This turns out to have been a mixture of valsartan and sacubitril, a neutral endopeptidase inhibitor, and most participants ended up receiving a daily dose of 320mg of valsartan, versus 20mg of enalapril. A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died after a median follow-up of 27 months, at which point the trial was stopped prematurely. So just what are we looking at here? How can we distinguish the effect of the sacubitril from the effect of the high dose of valsartan? Well, we can’t. And this trial is a perfect example of everything that is wrong with heart failure trials. The mean age of the 8442 patients was 63.8, nearly  80% were male, and they were selected by reduced ejection fraction in 1043 centres across 47 countries. A logistic nightmare, but a great way for Novartis to spread influence. And Novartis then collected, managed and analyzed all the data itself. As I have said, a submaximal dose of one drug was compared with a maximal dose of another plus an extra ingredient. There was a run-in period, in which patients who were intolerant to the new treatment (12%) dropped out. Adding bias to bias, the trial was terminated prematurely. One of the primary end-points was hospitalization, which was ably demolished in a JAMA article I pointed out last week. And yes, there was a mortality benefit, but the number-needed-to-treat was about 35 to prevent one death in 2 and half years, in a population far removed from the elderly co-morbid patients we see in real life. As I draw to the end of a clinical career in which I’ve tried to help people with heart failure, I stand bemused. This is just how things have been done for the last 30 years, and it’s not good enough. At the very least, Novartis must make its full data set available for independent analysis. And before sacubitril is licensed, we need a properly designed trial, say between valsartan 160mg b.d. alone and valsartan plus sacubitril, in a typical population with heart failure. It will be very interesting to see what the FDA, the EMA and NICE decide.
 
References
1.  Jessup M. Neprilysin inhibition - a novel therapy for heart failure.  N Engl J Med 2014;  DOI: 10.1056/NEJMe1409898.  Link here.
2.  McMurray JJV, Packer M, Desai AS et al.  Angiotensin - neprilysin inhibition versus enalapril in heart failure.  N Engl J Med 2014; DOI: 10.1056/NEJMoa1409077  Link here.
3.  Smith R. Medical journals are an extension of them marketing arms of pharmaceutical companies.  PLoS Medicine 2005;  DOI: 10.1371/journal.pmed.0020138.  Link here.
4.  Pablos-Mendez A, Barr G, Shea S. Run-in periods in randomized trials: implications for the application of results in clinical practice.  JAMA 1998;  279(3): 222-225. doi:10.1001/jama.279.3.222.  Link here.