The Latest Example of the Anechoic Effect - AllTrials US Initiative Launches to Deafening Media Silence

AllTrials anechoic effect suppression of medical research

The Latest Example of the Anechoic Effect - AllTrials US Initiative Launches to Deafening Media Silence

Unknown 8/11/2015 Komentar

Every now and then, someone tries to persuade me how much more open discussion of various kinds of recent unpleasantness in health care has become in the US. I admit there has been more media attention to certain issues, but unfortunately must maintain that the issues most likely to be make those who profit the most from our current health care system uncomfortable remains anechoic. Now I have my latest example

AllTrials

AllTrials is a UK based organization that advocates for registration and public reporting of all clinical trials.  AllTrials explains the reasons for this simply:

Clinical trials are the best way we have of testing whether a medicine is safe and effective. They can involve thousands of people, patients and healthy volunteers, and take years to complete.

Results from around half of all clinical trials remain hidden

Trials with negative results are twice as likely to remain unreported as those with positive results. This means that people who make decisions about medicines don’t have full information about the benefits and risks of treatments we use every day. Read our 8 page briefing note on missing trials here.

Thousands of clinical trials have never been publicly registered

There is no complete list of all clinical trials, so we don’t even know that some trials have taken place, never mind what was found in them.

The contributions of hundreds of thousands of patients are unused and unusable

Patients volunteer for clinical trials because they expect that what was found in the trial will be of use to doctors who make decisions about treatments and to researchers who are studying the condition. Trial participants have told us that the culture of secrecy around clinical trial reporting is a betrayal of their trust. Read their words here.

AllTrials has garnered considerable support in the UK.

On Health Care Renewal, we have been discussing the problem of suppressed clinical research for a long time, and have made similar arguments.  Up to now, I have chosen not to post a lot about AllTrials because as a UK based movement, it was getting considerable press coverage in the UK, and garnering considerable support there.  I did not think the movement needed what meager help a Health Care Renewal post would provide.

The Anechoic AllTrials USA Launch

But now, AllTrials has come to America.  And it perhaps should not be a surprise that its advent on this side of the pond generated essentially no notice, particularly, no notice in the US mainstream media or in US scholarly health care and medical journals.  

The announcement of the AllTrials US initiative appeared on the organization's website, and on the Biomed Central blog..  A press release appeared on the PRNewswire.  The American Academy of Family Practice (AAFP) announced its participation on its website.   The move received support from a post on the PLoS Public Health Perspectives blog, and perhaps surprisingly, from the UK based Financial Times.

Otherwise, at least according to my web searching efforts, there has been silence.  I found nothing in major media outlets, nothing in medical journals, and even nothing on the websites of the few US professional societies other than the AAFP that are listed as AllTrials USA supporters (that is, the American College of Obstetricians and Gynecologists, American College of Physicians and the American College of Chest Physicians). 

The Anechoic Effect Continues

We have frequently discussed the anechoic effect, the phenomenon that information or discussion that could challenge or discomfit the powers that be in the US health care often generates no echoes.  In effect, suppression of clinical research in itself is an example of the anechoic effect.

Why might even discussion that allows that clinical research might be suppressed invoke the cone of silence?

Looking at AllTrials literature may not be too helpful in providing an answer to this question.  The AllTrials organization is adept at discussing the reasons that clinical trials should not be suppressed, but has been very diplomatic about why they actually are suppressed.

On the other hand, its seems logical that when clinical trials are sponsored by organizations, such as pharmaceutical, biotechnology and device companies, to assess their own products, company management might get strong incentives to ensure that such research ends up making their products look good.  Sponsored research could be manipulated (in terms of the formal hypotheses it tests, its design, implmentation, and analysis) to increase the likelihood that the results would favor the sponsor.  When all else fails, the sponsor could suppress research that fails to make its products look good.  There is at least suggestive evidence that this occurs.  For example, see the now classic study by Turner et al that showed that clinical research sponsored by pharmaceutical companies to assess their own antidepressants were much more likely to be published if the results favored their own products.

So I suspect that the management of many health care organizations, particularly but not exclusively pharmaceutical, biotechnology, and device companies may not be very comfortable discussing the problem of suppressed research, or with measures designed to uncover such research.  Further, as we have discussed frequently, such companies have financial arrangements with individual health care professionals, health care academics, academic health care organizations, and a variety of other organizations such as medical societies and patient-advocacy groups.  These arrangements can constitute individual and institutional conflicts of interest.  It is not impossible that such financial relationships might influence such individuals and groups to want to avoid the topic of research suppression.

Yet it is striking that the important AllTrials USA initiative, an offshoot of an organization that has certainly got some attention in another English speaking country, has generated NO media or medical/ health care journal coverage in the US so far.

We cannot expect any real improvement in the dysfunctional US health care system while it still appears to be taboo to discuss many of its most dysfunctional aspects.  True health care reform requires open and honest discussion of these issues, that is, we need real free speech and a real free press in health care.  

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

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Praluent, the Next Expensive "Game Changer," Blockbuster," "New Hope," - But Not Yet Shown to Benefit Patients

aliromucab evidence-based medicine health care prices manipulating clinical research PCSK9 inhibitor Praluent Regeneron Sanofi-Aventis

Praluent, the Next Expensive "Game Changer," Blockbuster," "New Hope," - But Not Yet Shown to Benefit Patients

Unknown 8/06/2015 Komentar

Here we go again.  The same month that it approved Entresto (look here), the US Food and Drug Administration approved a new PCSK9 inhibitor cholesterol lowering agent, alirocumab, immediately marketed as the pricy Praluent by Sanofi and Regeneron, and heralded by a blast of media hype.  Yet the evidence that this drug benefits patients is lacking, and critical review of the one big published randomized controlled trial of it raises many concerns.

Media Hype

Let us first consider the media hype.  The TIME coverage started with this headline,

This New FDA-Approved Cholesterol Drug is a Game Changer

The New York Times article by Andrew Pollack quoted Katherine Wilemon, founder and president of the FH foundation, an advocacy group for patients with familial hypercholesterolemia, who have very high cholesterol values and increased risk of heart and vascular disease,

It represents a new era of hope for us.

The Washington Post article started with,

The Food and Drug Administration on Friday approved the first in a new class of cholesterol-busting drugs that many doctors believe will trigger a breakthrough in reducing the incidence of strokes and heart attacks, which kill hundreds of thousands of Americans each year.

USA Today reported,

The drugs are predicted to be blockbusters many times over, adding billions of dollars to prescription drug costs, said Steve Miller, senior vice president and chief medical officer at Express Scripts, a leading pharmacy benefit manager.

Another NY Times article by Gina Kolata directly described the drug as

powerful almost beyond belief.

Ms Colata also quoted a cardiologist who characterized the drug again as a "game changer."

To be fair, note that while the WaPo article, NYT article by Pollack and the USA Today article provided hype attributed to "doctors," or identified individuals, they also quoted some people who were very skeptical about the drug.  However, in most of the media coverage, the positivity seemed to be more prominent and extreme than the skepticism. 

The High Price

In general, the media coverage noted that the "breakthrough," "blockbuster," "powerful" new drug would not come cheap.  Praluent would cost about $14,600 a year.  Naturally, those selling it saw this as a bargain.  For example, Andrew Pollack wrote in the NYT,

Sanofi and Regeneron Pharmaceuticals, which developed the product, said the price was justified by the potential benefits to patients and savings to the health care system that the drug would provide by preventing heart attacks and strokes — though the ability of the drug to do that has not been proved.

'We came to a price that is reflective of value, not what the market will bear,' said Elias Zerhouni, head of research and development at Sanofi, who said his own brother had suffered three heart attacks and needed new options to control cholesterol.

Gina Kolata went farther,

The $14,600 yearly price of the drug, which is injected under the skin once every two weeks, is a stunner. Yet for some patients, that might actually be a bargain.

She justified this by comparing the cost to apheresis, a radical procedure to treat high cholesterol. She did not discuss whether it had any evidence of clinical benefit. Yet,

'Cost is in the eye of the beholder,' said Dr. Daniel Soffer, [Mr. DeRuchie’s cardiologist at the University of Pennsylvania.

Presumably, Dr Soffer was the one who had recommended the apheresis treatment.

Note that at best, the company that sells this drug can justify the price only in terms of potential, not actual value or results.  

No Evidence for Clinical Benefit

Praluent, generic name alirocumb, is certainly a breakthrough in that it seeks to lower cholesterol through a novel mechanism.  The drug is a biologic, a monoclonal antibody that inhibits the enzyme PCSK9.

Yet a close reading of the one large published randomized controlled trial of alirocumab(1) belays the hype beyond that.  The study by Robinson et al was a double blind randomized controlled trial of alirocumab injections every 2 weeks versus placebo.  The protocol called for patients to be treated for 78 weeks, and followed for 8 more weeks, a bit more than one and one-half years.

Loss to Follow Up and Missing Data

The study enrolled 1553 patients in the alirocumab group, and 788 in the placebo group.  However, many patients did not complete the study: a total of 437 (28.1%) in the alirocumab group, and 193 (24.5% in the placebo group).  Reasons for noncompletion were adverse events (113, 7.2% alirocumab vs 47, 6.0% placebo); "nonadherent" to treatment (60, 3.9% vs 38, 4.7%), and "other reason," (264, 17.0% vs 108, 13.7%).

So the drop out rate was fairly high.  It was particularly troubling that the reasons for most of the drop outs were vague "other reaons."  I could not find a clarification of this term in the main article or  supplemental materials.

Furthermore, it was not clear how the investigators intended to collect data from patients after they dropped out, and how complete data collection about clinical events was for patients who dropped out.  (Note that for patients that dropped out, the investigators simply imputed, that is estimated cholesterol values, but did not necessarily measure them.  So even this measure was "potential.")

Drop outs and missing data are classically problematic because patients may drop out after suffering  events that could be counted as study outcomes.  The rate of these events could differ according to treatment group.  If patients who dropped out of the alirocumab group had more adverse events than those who dropped out of the placebo group, and these events were not recorded, the high drop out rate could have concealed important harms of the drug.

Thus it is quite possible that the study by Robinson et al undercounted adverse events due to aliromucab.

Multiple Study Sites

The study enrolled patients at a remarkable number of sites, 320 in 27 countries, so that the average number of patients enrolled per site was only seven.    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.  I could not find a discussion of implementation quality control in the published article.

Thus it is possible that poor quality of study implementation, which could have affected enrollment and data collection, may have challenged the validity of the Robinson et al study.

 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.

Common conditions leading to exclusion were:
- Recent heart and cardiovascular problems, i.e., "(within 3 months prior to the screening visit [Week -3] or between screening and randomization visits) MI, unstable angina leading to hospitalization, uncontrolled cardiac arrhythmia, CABG, PCI, carotid surgery or stenting, cerebrovascular accident, transient ischemic attack, endovascular procedure or surgical intervention for peripheral vascular disease."
- "Planned to undergo scheduled PCI, CABG, carotid or peripheral revascularization during the study"
-  Severe congestive heart failure, i.e., "New York Heart Association Class III or IV heart failure within the past 12 months"
- Poorly controlled hypertension, i.e., "Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg at screening visit or randomization visit."
- "History of hemorrhagic stroke."
- "History of active optic nerve disease."
- Use of systemic corticosteroids, other than for replacement 
- "History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer."
- "History of HIV positivity."
-   "Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody (confirmed by reflexive testing)."
- Kidney dysfunction, specifically, "eGFR <30 nbsp="" p="">- Poorly controlled diabetes, specifically, HbA1c >10%.
- Abnormal liver enzymes, specifically, ALT or AST > x ULN

Vaguely described exclusions were:

E 25. Conditions/situations such as:
A) Any clinically significant abnormality identified at the time of screening that in the
judgment of the Investigator or any sub-Investigator would preclude safe completion
of the study or constrain endpoints assessment such as major systemic diseases,
patients with short life expectancy.
B) Patients considered by the Investigator or any sub-Investigator as inappropriate
for this study for any reason, e.g.:
i) Those deemed unable to meet specific protocol requirements, such as scheduled
visits.
ii) Those deemed unable to administer or tolerate long-term injections as per the
patient or the investigator.

Also,

iv) Presence of any other conditions (eg, geographic, social….) actual or anticipated,
that the Investigator feels would restrict or limit the patient’s participation for the
duration of the study.

Thus the study would have excluded patients with a variety of common conditions, and may have excluded many other patients based on rather poorly defined decisions by individual investigators.  Since patients in clinical practice commonly have common conditions, the generalizability of the results of this study to many practices and patients was not clear.

No Evidence of Clinical Benefit

Patients should not be subject to treatments whose benefits do not clearly outweigh their harms.  The Robinson et al article focused on reductions in measured cholesterol, particularly LDL cholesterol.  The new drug certainly did seem to clearl reduce cholesterol, particularly LDL cholesterol.  However, these are only the results of laboratory tests.

Although high cholesterol and high LDL cholesterol indicate increased risk of future cardiac events, many patients with abnormal values do not have such events.  Having a high cholesterol or LDL cholesterol does not directly cause symptoms, or dysfunction.  Thus simply lowering cholesterol does not immediately or directly benefit patients.  Furthermore, other drug have been shown to lower cholesterol, but ultimately they accomplished this without ever being shown to benefit patients, e.g., by preventing heart attacks, strokes, or premature death.

However, cholesterol values are considered intermediate or surrogate variables.  They are not directly related to what happens to patients, who they feel or function, whether they get new diseases, or when they die.  So only showing that the new drug lowers cholesterol does not prove clinical patient benefit.

Although the published trial did attempt to record cardiovascular events, it did not find that the drug prevented them.  The small difference in total cardiovascular events affecting patients given alirocumab (4.6%) versus placebo (5.1%) did not reach statistical significance, that is, could well have been due to chance alone.

Furthermore, while elevated cholesterol is a chronic problem, and the problems with which it is correlated occur over the long run, the study ran for less than 2 years.  It could not measure the effects of the new drug beyond that.

So the clinical benefit of the drug was not evident in this trial.

On the other hand, the drug was not without its own risks.  More patients who received aliromucab left the study due to adverse events (7.2%) thand did those who got placebo (5.8%),  as noted above.  Also, as noted above, it was possible that adverse events affecting dropouts were not fully recorded.  Given that there were higher rates of dropouts due to non adherence and "other" reasons among patients who received alirocumab, the study might still have missed important adverse effects of the new drug.

So the study did not prove that the new drug has any clinical benefits, showed it does have clinical harms, and could still have easily underestimated its harms.  So it certainly did not show it had benefits that outweighed its harms.

Summary and Conclusions

The NEJM study was accompanied by an editorial by Stone and Lloyd-Jones(2) which documented that drugs previously shown to lower cholesterol were never proved to do any good for patients, and concluded,

it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary end-point analysis and safety assessment, are available. 

After an FDA advisory committee recommended approval of aliromucab in June, 2015, John Mandrola entitled a Medscape article,

Dear FDA: Resist the Urge on PCSK9 Drugs

His reasons included lack of proof of clinical benefits, and concerns that harms may have been missed but mainly because of its inability to detect long-term outcomes.


Again, the current media articles also noted the concerns raised by Dr Mandrola and the NEJM editorial These concerns, however, did not dissuade the FDA from approving aliromucab.  These concerns did not apparently affect the pricing of Praluent.  These concerns will likely not deter the drug manufacturers from continuing an aggressive marketing campaign.  Whether these concerns will deter physicians from prescribing, or patients from asking for these drugs is unknown, but unlikely.

And I have not seen anything published so far that addressed how the problem with dropouts and missing data may have lead to further underestimation of aliromucab's harms, the multiplicity of study sites may have lead to quality control problems further challenging the study's validity, and the extensive exclusion criteria may have reduced the study's generalizability.

So here we go again.  Another new drug is put on the market accompanied by a mighty hoopla, yet in the absence of clear data that it does more good for patients than harm.

As we said last year about valsartan-sacubitril, also just (July, 2015) put on the market as Entresto, at a high price and with lots of hype,...

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 could lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.


How high must our health care costs go, and how many unproven treatments must eventually be exposed as such before we learn that lesson?

ADDENDUM (6 August, 2015) - Fixed minor errors: misspelling of Ms Kolata's name fixed, misstatement re apharesis fixed, erroneous reference to second approved PCSK9 inhibitor removed.  

ADDENDUM (9 August, 2015) - Note that his post was republished on the Naked Capitalism blog.  


References
1. Robinson JG, Farnier M, Krempf M et al.  Efficacy and safety of alirocumab in reduincg lipids and cardiovascular events.  N Engl J Med 2015; 372: 1489-1499.  Link here.
2.  Stone NJ, Lloyd-Jones DM.  Lowering LDL cholestero is good, but how in whom?  N Engl J Med 2015; 372: 1564-5.  Link here.  

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60% of the CEOs of America's "Great Health Systems" Have No Educational Background in Health Care

generic managers hospital systems

60% of the CEOs of America's "Great Health Systems" Have No Educational Background in Health Care

Unknown 8/01/2015 Komentar

We have noted that US health care has been taken over by generic managers.  A recent article about the CEOs of purportedly some of America's best hospitals provides some quantitative data.

A few days ago, Becker's Hospital Review published a list of the educational background of the CEOs of the "50 great health systems to know | 2015," (at least according to Becker's.  The article noted that their educational experiences took place at,

Ivy League schools, small liberal arts colleges, Big Ten universities, law schools, medical schools and more.

That is nice, but I decided to simply look at how many of the CEOs had educational backgrounds in medicine, other health care professions, public health, or the biomedical sciences.

Here is the breakdown of their most advanced degrees:

16 (32%) had medical doctorates
26 (52%) had a business administration degree, all but one at the master's level, and one a doctorate. 

The rest had various masters  and doctoral degrees in other fields. 

Note that two of the MDs also had MBAs, and one had a JD (law degree).

The business administration degrees included MBAs, but also degrees in health, hospital administration.  Of those with these degrees, one also had a bachelors degree in pharmacy, and one in biology.

One CEO was listed as attending a nursing school, but no degree or certificate from that experience was listed.

Comment

In any case, the majority, more than 60% of the CEOs of some of America's most prestigious hospitals (by at least one measure) clearly had no educational background in medicine, another health profession, public health, or biomedical science.  Again, this demonstrates that the top leaders of the top US health care organizations are more often management, rather than medicine, health professional.

This is corroborated by other observations.  In 1988, Alain Enthoven advocated in Theory and Practice of Managed Competition in Health Care Finance, a book published in the Netherlands, that to decrease health care costs it would be necessary to break up the "physicians' guild" and replace leadership by clinicians with leadership by managers (see 2006 post here). Thus from 1983 to 2000, the number of managers working in the US health care system grew 726%, while the number of physicians grew 39%, so the manager/physician ratio went from roughly one to six to one to one (see 2005 post here). As we noted here, the growth continued, so there are now 10 managers for every US physician.

Why is this a problem?   The managers who first took over health care may have had some health care background.  Now it seems that health care managers are decreasingly likely to have any health care background, and increasingly likely to be from the world of business.  Meanwhile, for a long time, business schools seem to have been teaching managers that they have a God given right to manage every organization and every aspect of society, regardless how little they know about what the particular context, business, calling, etc involves.  Presumably this is based on a faith or ideology that modern management tools are universally applicable and nigh onto supernatural in their powers.  Of course, there is not much evidence to support this, especially in health care.

We have discussed examples of bizarre proclamations by generic managers that seem to corroborate their belief in such divine powers.  Most recently, there was the multimillionaire hospital system CEO (who is on the list, and whose highest non-honorary degree is a masters in philosophy and political science) who proclaimed new artificial intelligence technology could replace doctors in short order (look here).    We have noted many cases of management of health care organizations that was ill-informed, and indifferent or even hostile to the core values of health professionals. 

I believe true health care reform would enable health care leadership by people who understand the actual care of patients, uphold health care professionals' values, and are willing to be accountable for putting patients' and the public's health first. 

But this sort of reform would challenge the interests of managers who are getting very rich off the current system.  (See some examples of grandiose executive compensation in health care here.)  So I expect lots of resistance to any proposals to push health care leaders to be more knowledgeable about health care and sympathetic to its values. 

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Entresto: Blockbuster, or Just Over Hyped? - Whatever, It Will Cost $4500 a Year

CHF clinical trials Entresto evidence-based medicine manipulating clinical research Novartis sacubitril

Entresto: Blockbuster, or Just Over Hyped? - Whatever, It Will Cost $4500 a Year

Unknown 7/30/2015 Komentar

The newest drug for congestive heart failure, Entresto, a fixed combination of valsartan and sacubitril, has just hit the market at an elevated price.  Like other drugs recently introduced as blockbusters, the high price does not seem clearly justified by clinical evidence about the drug's benefits and harms.  


Questions Raised by the One Big Published Controlled Trial

Last year, we discussed the hoopla around a study of a new drug for congestive heart failure (CHF),(1) a fixed combination of valsartan and sacubitril. Also, on the now defunct CardioExchange blog, Dr Vinay Prasad discussed the same study (look here, and scroll down.) We both concluded that the (apparently multiply flawed) design of the study left important questions unanswered.

Does Sacubitril Actually Work?

 The PARADIGM-HF study compared patients given valsartan plus sacubitril to patients given enalapril.  Valsartan, an angiotensin receptor blocker (ARB) and enalapril, an angiotensin converting enzyme inhibitor (ACEI) have both been shown separately to improve symptoms and function, decrease morbid events, and extend life for patients with systolic CHF.  However, the PARADIGM-HF study compared a high dose of valsartan, 160 mg twice a day, (plus sacubitril) to a medium dose of enalapril, 10 mg twice a day.  Apparently, no trial comparing just valsartan 160 mg to enalapril 10 mg twice a day has been done.  So it is quite possible that a high dose of valsartan is better than a medium dose of enalapril.  Thus, PARADIGM-HF could not prove that sacubitril has any benefit independent of high dose valsartan.

What are the Adverse Effects of Sacubitril (With or Without Valsartan) Likely to be in Practice?

The PARADIGM-HF design prevented any assessment of the adverse effects of sacubitril independent of those of valsartan.  Furthermore, the trial had an active run-in period which resulted in the exclusion of  patients who failed to tolerate valsartan-sacubitril in a pre-trial run-in period.  This effectively biased downward the prevalence of adverse effects due to the combination reported during the trial.  Finally, the trial, while big, was not big enough to discover rare but severe adverse effects.  Thus, one cannot easily tell how the benefits of valsartan-sacubitril compare to its harms, or how the benefits of sacubitril alone compare to its harms.

How Would Valartan-Sacubitril Work for Patients with Common Diseases in Addition to CHF?

The study excluded patients with common conditions that may afflict CHF patients, including relatively severe coronary artery disease, severe lung disease, ulcers and liver disease.  CHF patients are often elderly and often have other diseases, but how the drug might work for them is unclear.

Other Doubts and Questions

In a recent Medscape post, Dr John Mandrola noted additional problems with the study that raise doubts about its validity.  These included its early termination, the very large number (1000) of study sites raising doubts about quality control of implementation and data collection, and the finding, not emphasized by the authors, that valsartan-sacubril caused an apparent increase in hypotension, a significant issue for CHF patients.

As far as I can tell, there have been no other big trials of sacubitril, with or without valsartan, so there are no other source of clinical research data to address these questions.  As we noted here, one of the most prominent PARADIGM-HF investigators tried to rebut Dr Prasad, but did so mainly by employing logical fallacies.

So in my humble opinion, there is only weak, ambiguous data to show valsartan-sacubitril produces benefits that outweigh its harms for congestive heart failure patients seen in usual clinical practice.

More Enthusiasm and Hype about Entresto

These questions about the one big study of valsartan-sacubitril did not deter the US Food and Drug Administration (FDA) from approving it.  As soon as it was approved, the hype machine started up in a big way.

Per the NY Times,

'This is one of those once-in-a-decade kind of breakthroughs, to get a drug that extends life so substantially,' David Epstein, the head of Novartis’s pharmaceutical division, said in an interview.

Per the Wall Street Journal,

Clyde Yancy, chief of cardiology at Chicago’s Northwestern Memorial Hospital, said that Entresto is 'one of the few times that we have identified a medication that is better than the standard. It’s clearly superior to what we have.'

Per a Medscape news post, Dr Clyde Yancy also said,

A year later, I continue to feel that this is, in fact, a reflection of a new day—for patients and for the opportunity to reenergize the community. It's also a huge endorsement for the importance of science in cardiovascular medicine.

And Dr Milton Packer (who had countered Dr Pradad's critique of PARADIGM-HF with logical fallacies, said,

I think they considered the data to be compelling and strong. And I think that when physicians look at the data, they will be convinced that this drug will become a cornerstone of treatment for heart failure.

The Medscape article did document some doubts.  Dr John G Cleland of Imperial College, London, UK allowed that the active run-in group was among "issues that have yet to be settled," Dr Marriell Jessup who had written a positive editorial in the NEJM when the trial was published(2) allowed that the lack of patients with co-morbities might be a problem.  Finally, Dr Yancy allowed that the early termination might be a problem.   Yet each focused on a single problem with the study, and none of these physicians seemed to acknowledge the totality of the study's problem.  Neither did any of them seemed to let these doubts dampen the enthusiasm, e.g., at the end of the article, quoting Dr Yancy,

Can we change the narrative?  I believe it's time to take the 'failure' out of heart failure and look at what we can do to generate success.

Note that the article disclosed Dr Cleland does research funded by Novartis, maker of Entresto, and Dr Packer is a consultant to Novartis.  Is is possible these commercial relationships tempered any concerns that might have had about the study design. 

I realize that CHF is a miserable problem for patients, and clearly leads to severe symptoms, multiple hospitalization, and sometimes early death.  So I understand why people may be enthusiastic about a new therapy for it, especially if their research or consulting is funded by the drug's manufacturer.  But is it crystal clear the latest innovation is that good?

Billions of Dollars in Play

But never mind those unanswered questions and the multiple problems with the PARADIGM-HF trial, Entresto, the trade name for valsartan-sacubitril will not be cheap.  Per the NY Times,

Novartis said Entresto would cost about $12.50 a day, or about $4,500 for a year....

Novartis wants to convince you that it's not really that expensive

Mr Epstein said the price was 'really quite reasonable,' given that some drugs for other diseases cost many times that amount and confer less benefit.

He is certainly right that some drugs are even more expensive. However, is argument is just an appeal to common practice.  Whether the prices of other drugs are justified by strong evidence about their benefits and harms may not be clear. The benefits conferred by Entresto, and the harms it may cause as we belabored above, are really not that certain either. 

In the financial news, you could almost imagine the salivation.  Per the WSJ,

Wall Street predicts Entresto will be a blockbuster, with Leerink Partners estimating that annual global sales could top $6 billion by 2024.

In Reuters,

Expectations for Entresto have been building since it won early U.S. approval and Novartis set a higher than expected price, with analysts now forecasting $4.7 billion of sales in 2020, according to Thomson Reuters Cortellis.

Chief Executive Joe Jimenez said Entresto sales would take time to ramp up but growth would accelerate in 2016. Reception to the new drug, which Novartis started shipping within 24 hours of U.S. approval this month, has been good and there was little resistance to the $12.50 daily cost.

'The average hospital stay for a heart failure patient in the United States is $11,000,' Jimenez told reporters. 'So we are not receiving pushback on the price because I think this is seen as good value.'

Compared to what? Again, it is not clear that Entresto would be better than generic enalapril dosed at 20 mg/day, which is a lot cheaper than $4,500 a year.  But could it be that visions of billions of dollars have clouded some peoples' thinking, at least people paid by or owning stock in Novartis?

Summary

We have posted frequently about the blockbuster drug Sovaldi promoted as a cure for deadly hepatitis C infections.  Yet while the evidence that Sovaldi and its competitors are really so good, really provide cures, and really will prevent many patients from dire consequences of hepatitis C is not so strong, the US price of these drugs is stratospheric.

Now we have Entresto, whose price is not so stratospheric, but still quite high, and whose benefits compared to its harms are not clearly supported by evidence from clinical research.

 Unfortunately, Entresto (valsartan-sacubitril) is now one of a long line of new drugs that are breathlessly hyped, often by people who should know better, despite weak evidence in their favor.  It is one of a long list of examples of drugs approved based on poorly designed studies whose design flaws seem likely to make their commercial sponsors' products look better.  As a recent post in Health Affairs by Christopher Robertson reminds us, while many industry supporter act like allowing drug and device manufacturers to support (and usually control) most of the clinical research meant to evaluate their own products in inevitable,

When one steps back from our current practices, it should appear rather odd that we rely on companies to test the safety and efficacy of their own products. It would be as if a litigant were allowed to choose and fund its own judge, or an athlete to hire her own referee.

To convince us that we live in the best of all possible worlds, however, the media is full of proclamations that we are in a new era of marvelous medical and health care "innovations" that will bring us all untold benefits.  The notion that physician-industry collaboration is necessary to continue to produce these wondrous "innovations" is a talking point used to counter those who criticize conflicts of interest affecting academic medicine (look here).   Yet the evidence supporting many game-changers and blockbusters is often weak and ambiguous.  This rarely seems to deter the drug, device and biotechnology industry from charging more and more for them.


The sober, evidence-based medicine approach is being lost in all the hoopla and hucksterism.  We are adopting treatments of unproven value, whose benefits may be much less, and harms may be much worse than we imagine, and paying unconscionsable prices for them.  The results for patients and society include our ever rising health care costs, ever challenged access, and no evidence that outcomes are better for patients.

True health care reform would encourage sober discussion of the evidence, of benefits and harms, and of fair pricing, and would challenge the hype, hucksterism, and conflicts of interest that all swirl around modern health care. 



References

1.   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.

2.  Jessup M. Neprilysin inhibition - a novel therapy for heart failure.  N Engl J Med 2014;  DOI: 10.1056/NEJMe1409898.  Link here.

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What They Really Think of Us, UK Version - Health Secretary Derides NHS Doctors for Not Working Enough on Weekends

generic managers ill-informed management NHS UK

What They Really Think of Us, UK Version - Health Secretary Derides NHS Doctors for Not Working Enough on Weekends

Unknown 7/26/2015 Komentar

A new story from the UK suggests what top leaders of health care really think about health care professionals.  I realize that I risk showing my shallow understanding of UK politics when I comment on this, but I believe that the story is straightforward enough for someone from the US to understand, and has  lessons for the US and other countries.

UK Health Secretary Says Doctors Do Not Work Enough on Weekends

The story started earlier in July, 2016, when the current UK Health Secretary within the current Conservative government told National Health System (NHS) doctors they must work seven days a week, as reported by the Guardian,

The health secretary, Jeremy Hunt, has accused the main doctors’ union of walking out of NHS consultants’ [equivalent to US attending physicians] contract talks aimed at preventing 'catastrophic consequences' for patients at weekends.

Hunt said he recognised the efforts of consultants, many of whom already work on Saturdays and Sundays, but that he would impose weekend-working contracts by September if an agreement could be reached.

Also, 

The proposed contract would have at its core the controversial weekend working provision, but would include the abolition of overtime payments that Hunt has described as extortionate.

 Under the current contract, last negotiated by Labour in 2003, consultants can opt out of non-emergency work outside the hours of 7am to 7pm Monday to Friday.

Mr Hunt implied that insufficient physician presence on weekends was leading to catastrophe.

Hunt will say: 'Around 6,000 people lose their lives every year because we do not have a proper seven-day service in hospitals. No one could possibly say that this was a system built around the needs of patients and yet when I pointed this out to the BMA they told me to ‘get real.’ I simply say to the doctors’ union that I can give them 6,000 reasons why they, not I, need to ‘get real’.'

However, UK Doctors, Including Consultants, Do a Lot of Work on Weekends

Within a few days, there was an amazing response from UK physicians showing that what the Health Secretary seemed to believe about how NHS hospitals work was, not to put too fine a point on it, wrong.

From the Guardian came a piece by an anonymous trainee physician,

Last weekend, for the first time ever, I managed to make something trend on Twitter. It wasn’t a witty comment about Andy Murray triumphing in the Davis Cup, nor was it a retweet of a picture of somebody else’s cat.

I simply told a man called Jeremy that I was at work that night.

Three days later, thousands of people were telling Jeremy that they too were at work that weekend, using the hashtag #iminworkjeremy. Day and night, Friday to Monday, a large group of people felt Jeremy simply had to know what they were up to.

Because Jeremy is fairly important in the running of the country. Well, part of the country anyway – that part where the sick can just turn up and be treated without money changing hands. The part I work in, in fact, as a junior doctor.

Jeremy is concerned about how his part of the country is being run. He is upset that the ones who keep the sick alive – the doctors – aren’t there at weekends.

It’s just a pity Jeremy is wrong.

The Jeremy in question is, of course, secretary of state for health, the Rt Hon Jeremy Hunt, who last week announced he would bring in a 24-hour health service, seven days a week. To do this, he would alter consultant contracts to stop them including an 'opt-out' from weekend working – by force, if need be. To bolster his point, he told the public that there were not many consultants in at the weekends, and also that you were more likely to die if you came to hospital at a weekend.

I am not a consultant, far from it, but I do know that if and when I become a consultant, I will work weekends and I will be in at night. I accepted this when I took the role on.

So why did I, and the rest of my campaign group, tell the nation’s health workers to tell Mr Hunt that we were indeed working over the weekend?

I think, firstly, it was in answer to the claim that consultants do not work on Saturdays and Sundays. Our campaign has demonstrated that, day and night, there are doctors of all grades at work, often working unsociable hours.

The article also pointed out that having a consultant (the equivalent in the US of attending physician) available on the weekends may not lead to true seven day service if what the consultant orders is not available on weekends.

Two days later, another junior doctor's response to Mr Hunt had gone viral, as reported by the Mirror,

In an open letter, paediatric junior doctor Benjamin Carter, said health professionals felt 'upset, demoralised and feeling entirely unappreciated' after Mr Hunt painted them as 'lazy, money-grabbing, unprofessionals' who were opposed to 24-7 healthcare.

Also,

He said: 'Please allow me to paint a picture for you, as I am sure you are aware by now due to the #‎IminworkJeremy movement, a great many doctors work weekends. I for one tend to work 1 in every 3.

'This includes juniors and consultants, my consultants in particular have a rota for who is covering the weekends day and night because we need that expertise. When on call for that weekend, my consultants do ward rounds, they see sick children, they are present for the emergencies that their wealth of experience and knowledge helps resolve.

'They do not opt out, they do not complain, and they certainly do not go straight back to the golf course. They might not always be on site for the whole 72 hour weekend, but they are never more than a phonecall away.

'I look up to my consultants as pillars of excellence and professionalism. For you to say that we as a group operate with a lack of vocation and professionalism is not only false, it is gravely insulting.'

Dr Carter posted his letter to Facebook, where it has been shared more than 5,000 times in just a few hours.

In addition,

In a moving section, he explained that much of the anger aimed among doctors is because they have to deal with life and death on a daily basis, for a relatively modest wage.

He said: 'Already our pay is comparable to a high street manager [equivalent to a manager of a shop on Main St in the US], and that it pails in comparison to a city [equivalent in the US to Wall Street] worker and that neither of those professions require their workers to deal with life and death daily, to endure aggression from those we are trying to help and to be reduced to tears that result from exhaustion and the sheer emotional burden of our daily work.

'I invite you to come to my place of work and be there holding a dying child's hand and then tell me afterwards that I don't have a sense of vocation.'

A day later, a UK consultant calculated just how "extortionate" his overtime payments were, per the Independent,

A consultant angered by Health Secretary Jeremy Hunt's claims that a 'Monday to Friday' culture exists within the NHS has published an honest account of exactly how much he earns on call and at weekends.

Karan Kapoor posted the no holds barred letter to his Facebook page, describing what he takes home as a newly-appointed NHS ENT (Ear, Nose and Throat) consultant when working outside his usual hours.

His on-call supplement per month, he reveals, pays just £313.54 [currently = $532.49] - the equivalent of £2.61 [currently = $4.05] per hour and significantly less than the minimum wage. 

He concluded,

'I am genuinely offended that you have openly questioned my professionalism and vocation or that of my colleagues,' Mr Kapoor writes.

'I am no different to the thousands of Consultants, Junior Doctors, Nurses, Physios, Pharmacists, Secretaries, Speech Therapists, etc.

'We don't go on strike, we don't hold the country to ransom, we don't compromise patient care because we were meant to go home 2 hours ago, instead we go above and beyond, understanding the true meaning of professionalism and being exemplar to any health service in the world.

'Without this silent and diligent commitment, the NHS would have crumbled many years ago.'

The story also noted the groundswell of anger inspired by Mr Hunt's implication that today's NHS doctors do not work on weekends,

Last week a petition to call a debate on a vote of no confidence in the Health Secretary hit 100,000 - the required number of signatures to be considered for debate in Parliament - in less than 24 hours.

The petition, which was started by Dr Ash Sadighi, argues that Mr Hunt has 'alienated the entire workforce of the NHS' with his plans 'to impose a harsh contract and conditions on first consultants and soon the rest of the NHS staff.'

Finally, the Independent documented another online outburst generated by a consultant surgeon posting a picture of "himself moping a hospital floor" on Facebook.

What Generic Managers Really Think of Health Professionals

We have frequently discussed how US health care has been taken over by generic managers.  In 1988, Alain Enthoven advocated in Theory and Practice of Managed Competition in Health Care Finance, a book published in the Netherlands, that to decrease health care costs it would be necessary to break up the "physicians' guild" and replace leadership by clinicians with leadership by managers (see 2006 post here). Thus from 1983 to 2000, the number of managers working in the US health care system grew 726%, while the number of physicians grew 39%, so the manager/physician ratio went from roughly one to six to one to one (see 2005 post here). As we noted here, the growth continued, so there are now 10 managers for every US physician.

The managers who first took over health care may have had some health care background.  Now it seems that health care managers are decreasingly likely to have any health care background, and increasingly likely to be from the world of finance.  Meanwhile, for a long time, business schools seem to have been teaching managers that they have a God given right to manage every organization and every aspect of society, regardless how little they know about what the particular context, business, calling, etc involves.  Presumably this is based on a faith or ideology that modern management tools are universally applicable and nigh onto supernatural in their powers.  Of course, there is not much evidence to support this, especially in health care.

I have every reason to believe the idea that "professional" managers and business people should be in charge of all parts of society and all economic sectors has spread well outside the US.  UK Health Secretary Jeremy Hunt seems to be an example.  His background, according to the Gov.UK website, is that "Before his election as an MP, Jeremy ran his own educational publishing business, Hotcourses."  A Financial Times article noted that in 2014, he still had a major financial interest in the company,

Jeremy Hunt, the health secretary, has suffered a setback in his attempt to sell his education listings business after private equity group Inflexion pulled out of a proposed £35m deal.

Hotcourses, which claims to be the world’s largest database of educational courses, was set up by Mr Hunt and his business partner, Mike Elms, in 1996, before he entered parliament.

The article noted further, ironically in regard to the Mr Hunt's recent controversy,

The deal was an awkward reminder for the coalition of the large personal wealth of many cabinet ministers at a time when Labour has criticised the government for being 'out of touch' with ordinary voters.

As far as I could tell, before his political  career, Mr Hunt was a businessman with no experience or expertise in health care or biomedical science. And as of May, 2015, according to the the ThisIsMoney.uk website, Actually, he still seemed to be a businessman.  Mr Hunt still owned nearly half of the company, and was still receiving large dividend payments from it.

Nonetheless, Mr Hunt is now in charge of the whole of the British NHS.  However, his recent public pronouncement that NHS doctors do not work on weekends, and that is why the health service does not provide adequate services on weekends, reveals that he seems not to be very familiar with the organization he is supposed to be leading.  Again, we have seen many examples of leaders of big US health care organizations who seem ill-informed about their organizations, and sometimes hostile to their organization's health care mission.

However, we have not often heard a generic manager simultaneously publicly express so much hostility to health professionals  and so little knowledge about what those professionals actually do.  I suspect that is merely because many US managers are reined in better by their public relations departments and legal counsel. 

We are well into our global experiment involving handing control of virtually everything to managers, administrators, executives, and business people.  I submit it is not going well, and maybe leading us to some ultimate ruination.

As we have said again, again, again... It is way past time for health care professionals to take back health care from generic managers.  True health care reform would restore leadership by people who understand the health care context, uphold health professionals' values, are willing to be held accountable, and put patients' and the public's health ahead of self-interest. 

In the UK, doctors finally seem to be rising in protest against a particularly ill-informed businessman who is currently their boss.  It is past due for US doctors to hold to account similarly ill-informed, and sometimes also mission-hostile generic managers to whom they report.

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