Transparency International Reports on Massive Corruption in the Pharmaceutical Sector - Media Hardly Notices

anechoic effect deception health care corruption manipulating clinical research marketing pharmaceuticals suppression of medical research Transparency International

Transparency International Reports on Massive Corruption in the Pharmaceutical Sector - Media Hardly Notices

Unknown 6/08/2016 Komentar

Health Care Corruption as a Taboo Topic

Transparency International (TI) defines corruption as

Abuse of entrusted power for private gain

In 2006, TI published a report on health care corruption, which asserted that corruption is widespread throughout the world, serious, and causes severe harm to patients and society.

the scale of corruption is vast in both rich and poor countries.

Also,

Corruption might mean the difference between life and death for those in need of urgent care. It is invariably the poor in society who are affected most by corruption because they often cannot afford bribes or private health care. But corruption in the richest parts of the world also has its costs.

The report did not get much attention.  Since then, health care corruption has been nearly a taboo topic in the US.  When health care corruption is discussed in English speaking developed countries, it is almost always in terms of a problem that affects benighted less developed countries.  On Health Care Renewal, we have repeatedly asserted that health care corruption is a big problem in all countries, including the US, but the topic remains anechoic.

Yet somehow, a substantial minority of US citizens, 43%, seemed to believe that corruption is an important problem in US health care, according to a TI survey published in 2013 (look here).  But that survey was largely ignored in the media and health care and medical scholarly literature in the developed world, and when it was discussed, it was again in terms of results in less developed countries.  Health Care Renewal was practically the only source of coverage in the US of the survey's results.

Transparency International's New Report on Corruption in the Pharmaceutical Sector

Now Transparency International (TI) has tried, and Health Care Reenewal will try again.  In June, 2016 Transparency International published a new report entittled

Corruption in the Pharmaceutical Sector

The report's executive summary states:

Within the health sector, pharmaceuticals stands out as sub-sector that is particularly prone to corruption. There are abundant examples globally that display how corruption in the pharmaceutical sector endangers positive health outcomes.

In my humble opinion, the report is particularly significant in that it classifies as corrupt various kinds of activities that occur within the pharmaceutical sector (and also in other parts of health care) which are often discussed publicly as anything from standard operating procedure through unfortunate errors to unethical behavior. These include many activities which we have frequently discussed on Health Care Renewal. For example,

Manipulation of Clinical Research

We have frequently discussed how pharmaceutical companies, and biotechnology, medical device, and other health care companies and organizations, may manipulate clinical research to enhance the likelihood that is results will favor their products and marketing goals, even if the results are biased, inaccurate, could mislead physicians and patients, and ultimately harm patients.  The TI report included: 

As pharmaceutical companies rely on gaining market entry in order to recoup R&D costs, when there is a lack of oversight in clinical trial data publication a conflict of interest exists in which a pharmaceutical company may have an incentive to manipulate clinical trial data. When clinical trial data is manipulated medical literature can become biased with positive findings fabricated, positive findings exaggerated or negative results hidden. This can result in inadequate prescribing patterns because HCPs rely on clinical trial data to make decisions on which medicines to use to treat patients.

Suppression of Clinical Research

We have frequently discussed how health care organizations (as above) may outright suppress clinical research when the results fail to support their interests.  The TI report included:

Transparency and access to information through mandatory clinical trial registration, sanctions for not registering results or providing clinical trial information, and the publication of both positive and negative results are commonly discussed as helpful tools to curb corruption. With the European Medicines Agency (EMA) as a notable positive exception, public agencies and authorities do not require R&D-based pharmaceutical companies to make their raw data publicly available, making it impossible to verify whether the reported results are accurate. Based on laws and regulations clinical trial data is considered to be proprietary information, which allows pharmaceutical companies to conceal important data from the public domain.

Manipulation of the Dissemination of Clinical Research

We have frequently discussed how health care organizations may manipulate the dissemination of clinical research, through various forms of publications, presentations, courses, media summaries, etc, to favor their products and marketing goals, even if the results are misleading and could harm patients.  For example, a while back we discussed the problem of "ghost-written" articles appearing in scholarly journals. The TI report included:

The practice of ghostwriting is also a risk with clinical trials. Ghostwriting involves the writing of clinical trial publications by industry and then having a highly esteemed researcher pass these findings off as their own without disclosing their actual involvement with the authorship of the article. It is a common practice, particularly in industry led trials. Ghostwriting is done to increase the prestige and reputation of the findings, while simultaneously researchers are able to improve their reputation, which can lead to promotions. Clearly this practice can result in inaccurate results being published.

Deceptive Marketing

We have frequently discussed how marketing of pharmaceuticals (and nearly everything else in health care) may be deceptive, favoring companies' products and services, but again misleading health care professionals and patients, and ultimately risking patient harm.  In the extreme, pharmaceutical companies (and other health care organizations) may resort to bribes or kickbacks.  The TI report included:

There are several methods for a corrupt pharmaceutical company to unethically market its medicines. At its most simple a pharmaceutical company can bribe a HCP directly with payments so its medicines are more likely to be prescribed. More abstrusely individuals may include a pharmaceutical company’s medicine on the national list that is reimbursed by public funds, in return for an indirect bribe by being sent to inappropriate holiday destinations for lavish conferences.

Corrupt marketing practices also include pharmaceutical companies providing misleading information regarding the safety and efficacy of a medicine to influence doctors’ prescribing habits and encouraging off-label, unlicensed use to increase sales.

Other Topics

Finally, the report mentions such issues as the revolving door, regulatory capture, etc, etc, etc

A Striking, and Strikingly Anechoic Report

Again, while the report summarizes information that is likely familiar to most Health Care Renewal readers, what is striking is that it describes manipulation of clinical research, suppression of clinical research, manipulation of dissemination of clinical research, and deceptive marketing as corruption.  That is a sentiment rarely heard in the US, and one that appears nearly taboo.  

Demonstrating the strength of the taboo, this striking report has gotten almost no attention in the media or scholarly medical and health care literature in the developed English-speaking countries.  Let me note the important exceptions, however.

I learned of the report from a brief news item from the BMJ, the prestigious UK journal that seems most at the forefront of championing the integrity of medical and health care research.(1)  The only substantial news article I could find on the report was also from the UK, in the Independent.  Its sub-title is worth repeating:

Transparency International says corruption is making a few rich and wrecking the health of some of the world's poorest people

Also, there were brief articles in Reuters, and in (web-only) FiercePharma.  That is about it so far.

The report itself suggests why it has been so anechoic, just like nearly every other attempt to expose health care corruption to public discussion.  Essentially, there is so much money to be made through pharmaceutical (and by implication, other health care corruption) that the corrupt have the money, power, and resources to protect their wealth accumulation by keeping it obscure.  In the TI Report itself,

However, strong control over key processes combined with huge resources and big profits to be made make the pharmaceutical industry particularly vulnerable to corruption. Pharmaceutical companies have the opportunity to use their influence and resources to exploit weak governance structures and divert policy and institutions away from public health objectives and towards their own profit maximising interests.

Keep in mind that the money made from corruption does not just go to innocent peoples' retirement funds that are invested in pharmaceutical stocks.  It predominantly goes to top corporate executives and managers, and their cronies who preside over the corrupt practices.


I might as well repeat myself once again.  As I wrote in 2015,

If we are not willing to even talk about health care corruption, how will we ever challenge it? 

So to repeat an ending to one of my previous posts on health care corruption....  if we really want to reform health care, in the little time we may have before our health care bubble bursts, we will need to take strong action against health care corruption.  Such action will really disturb the insiders within large health care organizations who have gotten rich from their organizations' misbehavior, and thus taking such action will require some courage.  Yet such action cannot begin until we acknowledge and freely discuss the problem.  The first step against health care corruption is to be able to say or write the words, health care corruption.

Reference

1.  Torjesen I.  Group calls for more to be done to tackle corruption in the pharmaceutical industry. BMJ 2016;353:i3099. Link here.

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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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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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Two New Independent Reports on the Death of Dan Markingson, But Now What Will Happen?

anechoic effect AstraZeneca atypical anti-psychotics clinical trials conflicts of interest manipulating clinical research research subjects suppression of medical research University of Minnesota

Two New Independent Reports on the Death of Dan Markingson, But Now What Will Happen?

Unknown 3/26/2015 Komentar

Years after his death, there is now a little more clarity about the clinical trial in which Dan Markingson was enrolled when he died.  Whether this clarity will have any impact remains to be seen.

We most recently posted about the aftermath of Mr Markingson's death here, (and see posts in 2013 here, and in 2011 here.)  Very briefly, Mr Markingson was an acutely psychotic patient enrolled in a drug trial sponsored by Astra Zeneca at the University of Minnesota.  His enrollment was said to be voluntary although at the time he enrolled he had been under a stayed order that could have involuntarily committed him to care.  Despite his mother's ongoing and vocal concerns that he was not doing well on the study drug and under the care of trial investigators, he continued in the trial until he died violently by his own hand.  After his death, his mother Mary Weiss, friend Mike Howard, and University of Minnesota bioethics professor Carl Elliott campaigned for a fair review of what actually happened.  University managers not only rebuffed their concerns, but harshly criticized Professor Elliott, and ended up reprimanding him for "unprofessional conduct."

Two New Reports

In the last few weeks, two new independent reports on the case appeared.  Both vindicated the concerns and questions raised by Mary Weiss, Mike Howard, and Prof Elliott.

Association for Accreditation of Human Research Protection

One, called for by the University of Minnesota faculty senate, was by the Association for Accreditation of Human Research Protection,  and said that the university left research subjects "susceptible to risks that otherwise would be avoidable" (see this Minneapolis Star-Tribune article.)  Furthermore, according to a post in the Science Insider blog from the American Association for the Advancement of Science, it said,

[T]he external review team believes the University has not taken an appropriately aggressive and informed approach to protecting subjects and regaining lost trust,

Also, it said the university has been

assuming a defensive posture. In other words, in the context of nearly continuous negative attention, the University has not persuaded its critics (from within and outside the University) that it is interested in more than protecting its reputation and that it is instead open to feedback, able to acknowledge its errors, and will take responsibility for deficiencies and their consequences.

Finally, it noted a "climate of fear" in the Department of Psychiatry.

Office of the Legislative Auditor for the State of Minnesota

The second report, available in full here,was from the Office of the Legislative Auditor for Minnesota.  If anything, it was more damning. Its summary included,

the Markingson case raises serious ethical issues and numerous conflicts of interest, which University leaders have been consistently unwilling to acknowledge. They have repeatedly claimed that clinical research at the University meets the highest ethical standards and dismissed the need for further consideration of the Markingson case by making misleading statements about past reviews. This insular and inaccurate response has seriously harmed the University of Minnesota’s credibility and reputation.

It seemed to affirm in detail nearly all of Weiss', Howard's and Elliott's concerns.  It recommended that the University should suspend new psychiatric drug trials until the problems it identified were remedied (see Star-Tribune article here.)

Vindication, but Will It Lead to Progress?  

Taken together, these reports vindicate the work of Mr Markingson's mother, friend, and academic watchdog Professor Elliott and their supporters.  As the Star-Tribune reported,

'Over the past eleven years the University of Minnesota has made us feel as if we have no voice, no rights and absolutely nothing remotely called justice,' wrote Mike Howard, a close friend to Markingson’s mother, in a letter in the audit. 'This report is the first step toward accountability.'

The Minnesota Post added the response of Professor Elliott and a colleague,

'It’s nice to have an independent confirmation of what we’ve been telling the university for five years, but which they have refused to listen to,' he told MinnPost on Thursday.

Elliott said he is not convinced, however, that Kaler and other university leaders are going to take responsibility for what happened in the Markingson case — or take the necessary steps to fix the problem going forward.

'One of the most worrying findings in the report was the widespread belief on campus that the university leadership doesn’t care about human study subjects,' he said.

Leigh Turner, another U bioethicist who has also been outspoken about the issues raised by the Markingson case, expressed similar concerns. 'Can we expect reform from the very people who have done nothing for the past several years?' he said in a phone interview.

'I hope there’s some change,' he added. 'But the fact that [Markingson died in 2004] and it’s now 2015, I think hope has to be tempered with a dose of realism. There are some very powerful forces interested in minimizing the findings and suggesting that there are only minor things that need to be done.'

It appears there a several major remaining questions.

What Were the Underlying Causes?

Although both reports went into some detail about what happened to Mr Markingson, they seemed not to dwell on why it happened.  They did not seem to address relevant contextual factors, policies, and decisions.  For example, the report by the Office of the Legislative Auditor included,

We understand that the University of Minnesota has been and should continue to be an institution that delivers not only high quality medical care but also engages in cutting edge medical research— research that does pose risks to human subjects. In addition, we do not question the appropriateness of the University obtaining money from pharmaceutical and other medical companies to support that research. However, in every medical research study—whether supported with public or private money—the University must always make the protection of human subjects its paramount responsibility.

However, as we and many others more erudite have discussed frequently, clinical research that evaluates products or services made by the commercial sponsors of the research has proven to be highly susceptible to manipulation by these sponsors to increase the likelihood that the results will serve marketing purposes, and suppression if the manipulation fails to produce the wanted results.  Commercial sponsors often strongly influence the design, implementation, analysis and dissemination of clinical research.  Often their influence is mediated by financial relationships with individual researchers and with academic institutions who seem more and more beholden to outside sponsors, that is, by conflicts of interest.  The report by the Auditor noted pressures, including financial pressures on the physician who ran the study in which Mr Markingson was a subject to enroll more patients and keep them enrolled.  To protect patients better in the future, in my humble opinion the relationships among commercial sponsors, academic medical institutions, and individual researchers need further consideration.  Is the easy money supporting research coming from commercial firms with vested interests in the outcome of that research really worth the risks of biased results, hidden results, and to research subjects?   

Will Anything Change and Will Anyone be Held Accountable?

Once these two reports were delivered, it now seems to be up to university managers to make needed changes.  In general, these are the same managers who are described above as so "defensive," who not only ignored complaints, but appeared to try to silence those who complained.  If they are left in charge, why should we expect them to make any meaningful changes?  Instead, should they  not be held accountable for their actions?  

Will the University Cease Hostilities Against Dr Elliott?

Again, as noted above, university managers did not merely disagree with Professor Elliott.  They disparaged him, appeared to try to intimidate him, and reprimanded him.  It seems at the very least he is owed an apology.  So far, nothing in the news coverage suggests he has or will receive one.

Will Anyone Notice? 

So far, this case has gotten good coverage in Minnesota media.  However, it has largely been ignored in the national media.  Beyond Minnesota, I could only find mention in some blogs, e.g., in PharmaLot by Ed Silverman, and in Forbes by Judy Stone.  I have seen nothing in any US medical or health care journal, although the British Medical Journal did cover it in a news feature.  This case clearly has global implications, and ought to be considered one of the most important cases illustrating the perils of commercially sponsored human research, but it remains proportionately anechoic.

Summary

The latest reports seem only to confirm that clinical research at major academic institutions has gone way off track.  It now seems that in their haste to bring in external funding, university administrators and the academic researchers who are beholden to them have sadly neglected the protection of their own patients.  As we have said ad infinitum, true health care reform would turn leadership of health care organizations over the people who understand and are willing to uphold the mission of health care, and particularly willing to put patients' and the public's health, and the integrity of medical education and research when applicable, ahead of the leaders' personal interests and financial gain.

ADDENDUM (25 March, 2015) - See also numerous posts by Professor Elliott on the Fear and Loathing in Bioethics blog,  by Bill Gleason in the Periodic Table blog,  and by Mickey Nardo on the 1BoringOldMan blog. 

ADDENDUM (30 March, 2015) - Note that after receiving offline comments, I changed the first paragraph to emphasize the clarity is about the trial, rather than the patient's death, and second paragraph to clarify that the order to commit was stayed.

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